Inhibitors of cyclin-dependent kinase 7 (cdk7)

ABSTRACT

The present invention provides novel compounds of Formula (I) and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof. Also provided are methods and kits involving the compounds or compositions for treating or preventing proliferative diseases (e.g., cancers (e.g., leukemia, melanoma, multiple myeloma), benign neoplasms, angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases) in a subject. Treatment of a subject with a proliferative disease using a compound or composition of the invention may inhibit the aberrant activity of cyclin-dependent kinase (e.g., CDK7), and therefore induce cellular apoptosis and/or inhibit transcription in the subject.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/519,484, filed Apr. 14, 2017, which is a U.S. National StageApplication filed under 35 U.S.C. § 371 of International PatentApplication No. PCT/CN2015/091996, filed Oct. 15, 2015, which claims thebenefit of and priority to U.S. Provisional Patent Application No.62/064,737, filed Oct. 16, 2014, the contents of each of which arehereby incorporated by reference in their entirety.

BACKGROUND OF THE INVENTION

The members of the cyclin-dependent kinase (CDK) family play criticalregulatory roles in proliferation. Unique among the mammalian CDKs, CDK7has consolidated kinase activities, regulating both the cell cycle andtranscription. In the cytosol, CDK7 exists as a heterotrimeric complexand is believed to function as a CDK1/2-activating kinase (CAK), wherebyphosphorylation of conserved residues in CDK1/2 by CDK7 is required forfull catalytic CDK activity and cell cycle progression. In the nucleus,CDK7 forms the kinase core of the RNA polymerase (RNAP) II generaltranscription factor complex and is charged with phosphorylating theC-terminal domain (CTD) of RNAP II, a requisite step in genetranscriptional initiation. Together, the two functions of CDK7, i.e.,CAK and CTD phosphorylation, support critical facets of cellularproliferation, cell cycling, and transcription.

Disruption of RNAP II CTD phosphorylation has been shown topreferentially affect proteins with short half-lives, including those ofthe anti-apoptotic BCL-2 family. Cancer cells have demonstrated abilityto circumvent pro-cell death signaling through upregulation of BCL-2family members. Therefore, inhibition of human CDK7 kinase activity islikely to result in anti-proliferative activity.

The discovery of selective inhibitors of CDK7 has been hampered by thehigh sequence and structural similarities of the kinase domain of CDKfamily members. Therefore, there is a need for the discovery anddevelopment of selective CDK7 inhibitors. Such CKD7 inhibitors holdpromise as a therapeutic agent for the treatment of CLL and othercancers.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1E are a table of exemplary compounds of Formula I.

SUMMARY OF THE INVENTION

The present invention provides CDK inhibitors, more particularly CDK7,CDK12 and CDK13 inhibitors, and in particular selective CDK7 inhibitorsof Formula (I), and pharmaceutically acceptable salts, solvates,hydrates, tautomers, stereoisomers, isotopically labeled derivatives,and compositions thereof. The present invention further provides methodsof using the compounds of the invention, and pharmaceutically acceptablesalts, solvates, hydrates, tautomers, stereoisomers, isotopicallylabeled derivatives, and compositions thereof, to study the inhibitionof CDK7 and other CDK family members, and as therapeutics for theprevention and/or treatment of diseases associated with overexpressionand/or aberrant activity of CDK7 and other CDK family members. Incertain embodiments, the inventive compounds are used for the preventionand/or treatment of proliferative diseases (e.g., cancers (e.g.,leukemia, melanoma, multiple myeloma), benign neoplasms, angiogenesis,inflammatory diseases, autoinflammatory diseases, and autoimmunediseases) in a subject.

In one aspect, the present invention provides compounds of Formula (I):

and pharmaceutically acceptable salts, solvates, hydrates, tautomers,stereoisomers, and isotopically labeled derivatives thereof, whereinRing A, W, X, R^(1b), R², R³, R⁴, R⁵, R⁶, n, p, and subvariables thereofare as defined herein.

In another aspect, the present invention provides pharmaceuticalcompositions comprising a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, hydrate, tautomer, stereoisomer, orisotopically labeled derivative thereof, and optionally apharmaceutically acceptable excipient. In certain embodiments, thepharmaceutical compositions described herein include a therapeuticallyeffective amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, hydrate, tautomer, stereoisomer, orisotopically labeled derivative thereof. The pharmaceutical compositionmay be useful for treating and/or preventing a proliferative orinfectious disease.

In another aspect, the present invention provides methods for treatingand/or preventing proliferative diseases. Exemplary proliferativediseases include cancer (e.g., leukemia, melanoma, multiple myeloma),benign neoplasm, angiogenesis, inflammatory diseases, autoinflammatorydiseases, and autoimmune diseases. In other embodiments, the presentinvention provides methods for treating and/or preventing an infectiousdisease (e.g., a viral infection).

In still another aspect, the present invention provides methods ofdown-regulating the expression of CDK7 in a biological sample orsubject.

Another aspect of the invention relates to methods of inhibiting theactivity of CDK7 in a biological sample or subject.

The present invention also provides methods of inhibiting cell growth ina biological sample or subject.

In still another aspect, the present invention provides methods ofinducing apoptosis of a cell in a biological sample or a subject.

In yet another aspect, the present invention provides compounds ofFormula (I), and pharmaceutically acceptable salts, solvates, hydrates,tautomers, stereoisomers, isotopically labeled derivatives, andcompositions thereof, for use in the treatment of a proliferativedisease in a subject.

In yet another aspect, the present invention provides compounds ofFormula (I), and pharmaceutically acceptable salts, solvates, hydrates,tautomers, stereoisomers, isotopically labeled derivatives, andcompositions thereof, for use in the treatment or prevention of aninfectious disease in a subject. In certain embodiments, the infectiousdisease is a viral infection.

Another aspect of the present invention relates to kits comprising acontainer with a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, hydrate, tautomer, stereoisomer, orisotopically labeled derivative thereof, or a pharmaceutical compositionthereof. In certain embodiments, the kits described herein furtherinclude instructions for administering the compound of Formula (I), orthe pharmaceutically acceptable salt, solvate, hydrate, tautomer,stereoisomer, or isotopically labeled derivative thereof, or thepharmaceutical composition thereof.

In still another aspect, the present invention provides methods ofinhibiting other CDK family members, specifically CDK12 and/or CDK13,with a compound of Formula (I).

The details of one or more embodiments of the invention are set forthherein. Other features, objects, and advantages of the invention will beapparent from the Detailed Description, the FIGURES, the Examples, andthe Claims.

Definitions

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed., inside cover, andspecific functional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in ThomasSorrell, Organic Chemistry, University Science Books, Sausalito, 1999;Smith and March, March's Advanced Organic Chemistry, 5^(th) Edition,John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3^(rd) Edition, CambridgeUniversity Press, Cambridge, 1987.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, Z and E double bond isomers,and Z and E conformational isomers. Therefore, single stereochemicalisomers as well as enantiomeric, diastereomeric, and geometric (orconformational) mixtures of the present compounds are within the scopeof the invention. Unless otherwise stated, all tautomeric forms of thecompounds of the invention are within the scope of the invention.Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures including the replacement of hydrogen by deuterium ortritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention. Such compounds are useful, forexample, as analytical tools, as probes in biological assays, or astherapeutic agents in accordance with the present invention.

Where a particular enantiomer is preferred, it may, in some embodimentsbe provided substantially free of the corresponding enantiomer, and mayalso be referred to as “optically enriched.” “Optically-enriched,” asused herein, means that the compound is made up of a significantlygreater proportion of one enantiomer. In certain embodiments thecompound is made up of at least about 90% by weight of a preferredenantiomer. In other embodiments the compound is made up of at leastabout 95%, 98%, or 99% by weight of a preferred enantiomer. Preferredenantiomers may be isolated from racemic mixtures by any method known tothose skilled in the art, including chiral high pressure liquidchromatography (HPLC) and the formation and crystallization of chiralsalts or prepared by asymmetric syntheses. See, for example, Jacques etal., Enantiomers, Racemates and Resolutions (Wiley Interscience, NewYork, 1981); Wilen, et al., Tetrahedron 33:2725 (1977); Eliel, E. L.Stereochemistry of Carbon Compounds (McGraw-Hill, N Y, 1962); Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E. L.Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind. 1972).

The term “aliphatic” or “aliphatic group”, as used herein, denotes ahydrocarbon moiety that may be straight-chain (i.e., unbranched),branched, or cyclic (including fused, bridging, and spiro-fusedpolycyclic) and may be completely saturated or may contain one or moreunits of unsaturation, but which is not aromatic. Unless otherwisespecified, aliphatic groups contain 1-6 carbon atoms. In someembodiments, aliphatic groups contain 1-4 carbon atoms, and in yet otherembodiments aliphatic groups contain 1-3 carbon atoms. Suitablealiphatic groups include, but are not limited to, linear or branched,alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as(cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

The term “alkyl,” as used herein, refers to a monovalent saturated,straight- or branched-chain hydrocarbon such as a straight or branchedgroup of 1-12, 1-10, or 1-6 carbon atoms, referred to herein as C₁-C₁₂alkyl, C₁-C₁₀ alkyl, and C₁-C₆ alkyl, respectively. Examples of alkylgroups include, but are not limited to, methyl, ethyl, n-propyl,isopropyl, n-butyl, iso-butyl, sec-butyl, sec-pentyl, iso-pentyl,tert-butyl, n-pentyl, neopentyl, n-hexyl, sec-hexyl, and the like.

The terms “alkenyl” and “alkynyl” are art-recognized and refer tounsaturated aliphatic groups analogous in length and possiblesubstitution to the alkyls described above, but that contain at leastone double or triple bond, respectively. Exemplary alkenyl groupsinclude, but are not limited to, —CH═CH₂ and —CH₂CH═CH₂.

The term “alkylene” refers to the diradical of an alkyl group.

The terms “alkenylene” and “alkynylene” refer to the diradicals of analkenyl and an alkynyl group, respectively.

The term “methylene unit” refers to a divalent —CH₂— group present in analkyl, alkenyl, alkynyl, alkylene, alkenylene, or alkynylene moiety.

The term “carbocyclic ring system”, as used herein, means a monocyclic,or fused, spiro-fused, and/or bridged bicyclic or polycyclic hydrocarbonring system, wherein each ring is either completely saturated orcontains one or more units of unsaturation, but where no ring isaromatic.

The term “carbocyclyl” refers to a radical of a carbocyclic ring system.Representative carbocyclyl groups include cycloalkyl groups (e.g.,cyclopentyl, cyclobutyl, cyclopentyl, cyclohexyl and the like), andcycloalkenyl groups (e.g., cyclopentenyl, cyclohexenyl,cyclopentadienyl, and the like).

The term “aromatic ring system” is art-recognized and refers to amonocyclic, bicyclic or polycyclic hydrocarbon ring system, wherein atleast one ring is aromatic.

The term “aryl” refers to a radical of an aromatic ring system.Representative aryl groups include fully aromatic ring systems, such asphenyl, naphthyl, and anthracenyl, and ring systems where an aromaticcarbon ring is fused to one or more non-aromatic carbon rings, such asindanyl, phthalimidyl, naphthimidyl, or tetrahydronaphthyl, and thelike.

The term “heteroaromatic ring system” is art-recognized and refers tomonocyclic, bicyclic or polycyclic ring system wherein at least one ringis both aromatic and comprises a heteroatom; and wherein no other ringsare heterocyclyl (as defined below). In certain instances, a ring whichis aromatic and comprises a heteroatom contains 1, 2, 3, or 4independently selected ring heteroatoms in such ring.

The term “heteroaryl” refers to a radical of a heteroaromatic ringsystem. Representative heteroaryl groups include ring systems where (I)each ring comprises a heteroatom and is aromatic, e.g., imidazolyl,oxazolyl, thiazolyl, triazolyl, pyrrolyl, furanyl, thiophenyl pyrazolyl,pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, indolizinyl, purinyl,naphthyridinyl, and pteridinyl; (ii) each ring is aromatic orcarbocyclyl, at least one aromatic ring comprises a heteroatom and atleast one other ring is a hydrocarbon ring or e.g., indolyl, isoindolyl,benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl,benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, carbazolyl, acridinyl, phenazinyl,phenothiazinyl, phenoxazinyl, pyrido[2,3-b]-1,4-oxazin-3(4H)-one,5,6,7,8-tetrahydroquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl; and(iii) each ring is aromatic or carbocyclyl, and at least one aromaticring shares a bridgehead heteroatom with another aromatic ring, e.g.,4H-quinolizinyl. In certain embodiments, the heteroaryl is a monocyclicor bicyclic ring, wherein each of said rings contains 5 or 6 ring atomswhere 1, 2, 3, or 4 of said ring atoms are a heteroatom independentlyselected from N, O, and S.

The term “heterocyclic ring system” refers to monocyclic, or fused,spiro-fused, and/or bridged bicyclic and polycyclic ring systems whereat least one ring is saturated or partially unsaturated (but notaromatic) and comprises a heteroatom. A heterocyclic ring system can beattached to its pendant group at any heteroatom or carbon atom thatresults in a stable structure and any of the ring atoms can beoptionally substituted.

The term “heterocyclyl” refers to a radical of a heterocyclic ringsystem. Representative heterocyclyls include ring systems in which (I)every ring is non-aromatic and at least one ring comprises a heteroatom,e.g., tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl,piperidinyl, pyrrolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl,dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl,and quinuclidinyl; (ii) at least one ring is non-aromatic and comprisesa heteroatom and at least one other ring is an aromatic carbon ring,e.g., 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl; and(iii) at least one ring is non-aromatic and comprises a heteroatom andat least one other ring is aromatic and comprises a heteroatom, e.g.,3,4-dihydro-1H-pyrano[4,3-c]pyridine, and1,2,3,4-tetrahydro-2,6-naphthyridine. In certain embodiments, theheterocyclyl is a monocyclic or bicyclic ring, wherein each of saidrings contains 3-7 ring atoms where 1, 2, 3, or 4 of said ring atoms area heteroatom independently selected from N, O, and S.

The term “saturated heterocyclyl” refers to a radical of heterocyclicring system wherein every ring is saturated, e.g., tetrahydrofuran,tetrahydro-2H-pyran, pyrrolidine, piperidine and piperazine.

“Partially unsaturated” refers to a group that includes at least onedouble or triple bond. A “partially unsaturated” ring system is furtherintended to encompass rings having multiple sites of unsaturation, butis not intended to include aromatic groups (e.g., aryl or heteroarylgroups) as herein defined. Likewise, “saturated” refers to a group thatdoes not contain a double or triple bond, i.e., contains all singlebonds.

As described herein, compounds of the invention may contain “optionallysubstituted” moieties. In general, the term “substituted”, whetherpreceded by the term “optionally” or not, means that one or morehydrogens of the designated moiety are replaced with a suitablesubstituent. Unless otherwise indicated, an “optionally substituted”group may have a suitable substituent at each substitutable position ofthe group, and when more than one position in any given structure may besubstituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at eachposition. Combinations of substituents envisioned under this inventionare preferably those that result in the formation of stable orchemically feasible compounds. The term “stable”, as used herein, refersto compounds that are not substantially altered when subjected toconditions to allow for their production, detection, and, in certainembodiments, their recovery, purification, and use for one or more ofthe purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group (such as an alkyl, alkenyl, alkynyl,alkylene, alkenylene, alkynylene or the carbon atom of a carbocyclyl,aryl, heterocyclyl or heteroaryl) are independently deuterium; halogen;—(CH₂)₀₋₄R^(o); —(CH₂)₀₋₄OR^(o); —O—(CH₂)₀₋₄C(O)OR^(o);—(CH₂)₀₋₄CH(OR^(o))₂, —(CH₂)₀₋₄SR^(o); —(CH₂)₀₋₄Ph (where “Ph” isphenyl), which may be substituted with R^(o); —(CH₂)₀₋₄O(CH₂)₀₋₁Ph whichmay be substituted with R^(o); —CH═CHPh, which may be substituted with—R^(o); —NO₂; —CN; —N₃; —(CH₂)₀₋₄N(R^(o))₂; —(CH₂)₀₋₄N(R^(o))C(O)R^(o);—N(R^(o))C(S)R^(o); —(CH₂)₀₋₄N(R^(o))C(O)NR^(o) ₂; —N(R^(o))C(S)NR^(o)₂; —(CH₂)₀₋₄N(R^(o))C(O)OR^(o); —N(R^(o))N(R^(o))C(O)R^(o);—N(R^(o))N(R^(o))C(O)NR^(o) ₂; —N(R^(o))N(R^(o))C(O)OR^(o);—(CH₂)₀₋₄C(O)R^(o); —C(S)R^(o); —(CH₂)₀₋₄C(O)OR^(o);—(CH₂)₀₋₄C(O)SR^(o); —(CH₂)₀₋₄C(O)OSiR^(o) ₃;—(CH₂)₀₋₄—C(O)—N(R^(o))—S(O)₂—R^(o), —(CH₂)₀₋₄OC(O)R^(o);—OC(O)(CH₂)₀₋₄SR^(o)—, —SC(S)SR^(o); —(CH₂)₀₋₄SC(O)R^(o);—(CH₂)₀₋₄C(O)NR^(o) ₂; —C(S)NR^(o) ₂; —C(S)SR^(o); —(CH₂)₀₋₄OC(O)NR^(o)₂; —C(O)N(OR^(o))R^(o); —C(O)C(O)R^(o); —C(O)CH₂C(O)R^(o);—C(NOR^(o))R^(o); —(CH₂)₀₋₄SSR^(o); —(CH₂)₀₋₄S(O)₂R^(o);—(CH₂)₀₋₄S(O)₂OR^(o); —(CH₂)₀₋₄OS(O)₂R^(o); —S(O)₂NR^(o) ₂;—(CH₂)₀₋₄S(O)R^(o); —N(R^(o))S(O)₂NR^(o) ₂; —N(R^(o))S(O)₂R^(o);—N(OR^(o))R^(o); —C(NH)NR^(o) ₂; —P(O)₂R^(o); —P(O)R^(o) ₂; —OP(O)R^(o)₂; —OP(O)(OR^(o))₂; —SiR^(o) ₃; —(C₁₋₄ straight or branchedalkylene)O—N(R^(o))₂; or —(C₁₋₄ straight orbranched)alkylene)C(O)O—N(R^(o))₂, wherein each R^(o) may be substitutedas defined below and is independently hydrogen, deuterium, C₁₋₆aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur, or, notwithstanding the definitionabove, two independent occurrences of R^(o), taken together with theirintervening atom(s), form a 3-12-membered saturated, partiallyunsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, which may besubstituted as defined below.

Suitable monovalent substituents on R^(o) (or the ring formed by takingtwo independent occurrences of R^(o) together with their interveningatoms), are independently deuterium, halogen, —(CH₂)₀₋₂R^(•),-(haloR^(•)), —(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(•), —(CH₂)₀₋₂CH(OR^(•))₂;—O(haloR^(•)), —CN, —N₃, —(CH₂)₀₋₂C(O)R^(•), —(CH₂)₀₋₂C(O)OH,—(CH₂)₀₋₂C(O)OR^(•), —(CH₂)₀₋₂SR^(•), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂,—(CH₂)₀₋₂NHR^(•), —(CH₂)₀₋₂NR^(•) ₂, —NO₂, —SiR^(•) ₃, —OSiR^(•) ₃,—C(O)SR^(•), —(C₁₋₄ straight or branched alkylene)C(O)OR^(•), or—SSR^(•) wherein each R^(•) is unsubstituted or where preceded by “halo”is substituted only with one or more halogens, and is independentlyselected from C₁₋₄ aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. Suitabledivalent substituents on a saturated carbon atom of R^(o) include ═O and═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*₂))₂₋₃O—, or—S(C(R*₂))₂₋₃S—, wherein each independent occurrence of R* is selectedfrom hydrogen, C₁₋₆ aliphatic which may be substituted as defined below,or an unsubstituted 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Suitable divalent substituents that are bound tovicinal substitutable carbons of an “optionally substituted” groupinclude: —O(CR*₂)₂₋₃O—, wherein each independent occurrence of R* isselected from hydrogen, C₁₋₆ aliphatic which may be substituted asdefined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include deuterium,halogen, —R^(•), -(haloR^(•)), —OH, —OR*, —O(haloR^(•)), —CN, —C(O)OH,—C(O)OR^(•), —NH₂, —NHR^(•), —NR^(•) ₂, or —NO₂, wherein each R^(•) isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†); wherein eachR^(†) is independently hydrogen, C₁₋₆ aliphatic which may be substitutedas defined below, unsubstituted —OPh, or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(†), taken together with their intervening atom(s) form anunsubstituted 3-12-membered saturated, partially unsaturated, or arylmono- or bicyclic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^(†) are independentlydeuterium, halogen, —R^(•), -(haloR^(•)), —OH, —OR^(•), —O(haloR^(•)),—CN, —C(O)OH, —C(O)OR^(•), —NH₂, —NHR^(•), —NR^(•) ₂, or —NO₂, whereineach R^(•) is unsubstituted or where preceded by “halo” is substitutedonly with one or more halogens, and is independently C₁₋₄aliphatic,—CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

“Halo” or “halogen” refers to fluorine (fluoro, —F), chlorine (chloro,—Cl), bromine (bromo, —Br), or iodine (iodo, —I).

The term “one or more methylene units of the alkylene, alkenylene oralkynylene is optionally replaced with —O—, —S—, —S(═O)₂, or —NR^(X)—”as used herein means that none, one, more than one, or all of themethylene units present may be so replaced. Thus, for example, themoieties, —O—, —S—, and —NR^(X)— are included in this definition becausein each case they represent a C₁ alkylene (i.e., methylene) replacedwith —O—, —S—, or —NR^(X)—, respectively.

It should also be understood that reference to a variable or subvariablein Formula I (e.g., R², R⁴ or R⁵) being “an optionally substituted C₁-C₄alkylene, and an optionally substituted C₂-C₄ alkenylene or alkynylene,wherein: one or more methylene units of the alkylene, alkenylene oralkynylene other than a methylene unit bound to a nitrogen atom isoptionally and independently replaced with —O—, —S—, —N(R⁶)—, or—S(═O)₂—” is only intended to encompass chemically stable combinationsof optionally substitutions and replacements.

As used herein, the term “leaving group” is given its ordinary meaningin the art of synthetic organic chemistry and refers to an atom or agroup capable of being displaced by a nucleophile. Examples of suitableleaving groups include, but are not limited to, halogen (such as F, Cl,Br, or I (iodine)), alkoxycarbonyloxy, aryloxycarbonyloxy,alkanesulfonyloxy, arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy),arylcarbonyloxy, aryloxy, methoxy, N,O-dimethylhydroxylamino, pixyl, andhaloformates. In some cases, the leaving group is a sulfonic acid ester,such as toluenesulfonate (tosylate, —OTs), methanesulfonate (mesylate,—OMs), p-bromobenzenesulfonyloxy (brosylate, —OBs), ortrifluoromethanesulfonate (triflate, —OTf). In some cases, the leavinggroup is a brosylate, such as p-bromobenzenesulfonyloxy. In some cases,the leaving group is a nosylate, such as 2-nitrobenzenesulfonyloxy. Insome embodiments, the leaving group is a sulfonate-containing group. Insome embodiments, the leaving group is a tosylate group. The leavinggroup may also be a phosphineoxide (e.g., formed during a Mitsunobureaction) or an internal leaving group such as an epoxide or cyclicsulfate. Other non-limiting examples of leaving groups are water,ammonia, alcohols, ether moieties, thioether moieties, zinc halides,magnesium moieties, diazonium salts, and copper moieties.

These and other exemplary substituents are described in more detail inthe Detailed Description, FIGURES, Examples, and Claims. The inventionis not intended to be limited in any manner by the above exemplarylisting of substituents.

Other Definitions

The following definitions are more general terms used throughout thepresent application:

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference. Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from suitable inorganic and organicacids and bases. Examples of pharmaceutically acceptable, nontoxic acidaddition salts are salts of an amino group formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid, and perchloric acid or with organic acids such as acetic acid,oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, ormalonic acid or by using other methods known in the art such as ionexchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄ alkyl)₄ ⁻ salts.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, lower alkyl sulfonate, and aryl sulfonate.

The term “solvate” refers to forms of the compound that are associatedwith a solvent, usually by a solvolysis reaction. This physicalassociation may include hydrogen bonding. Conventional solvents includewater, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and thelike. The compounds of Formula (I) may be prepared, e.g., in crystallineform, and may be solvated. Suitable solvates include pharmaceuticallyacceptable solvates and further include both stoichiometric solvates andnon-stoichiometric solvates. In certain instances, the solvate will becapable of isolation, for example, when one or more solvent moleculesare incorporated in the crystal lattice of a crystalline solid.“Solvate” encompasses both solution-phase and isolable solvates.Representative solvates include hydrates, ethanolates, and methanolates.

The term “hydrate” refers to a compound which is associated with water.Typically, the number of the water molecules contained in a hydrate of acompound is in a definite ratio to the number of the compound moleculesin the hydrate. Therefore, a hydrate of a compound may be represented,for example, by the general formula R.x H₂O, wherein R is the compoundand wherein x is a number greater than 0. A given compound may form morethan one type of hydrates, including, e.g., monohydrates (x is 1), lowerhydrates (x is a number greater than 0 and smaller than 1, e.g.,hemihydrates (R.0.5H₂O)), and polyhydrates (x is a number greater than1, e.g., dihydrates (R.2H₂O) and hexahydrates (R.6H₂O)).

The term “tautomers” refer to compounds that are interchangeable formsof a particular compound structure, and that vary in the displacement ofhydrogen atoms and electrons. Thus, two structures may be in equilibriumthrough the movement of π electrons and an atom (usually H). Forexample, enols and ketones are tautomers because they are rapidlyinterconverted by treatment with either acid or base. Another example oftautomerism is the aci- and nitro-forms of phenylnitromethane that arelikewise formed by treatment with acid or base.

Tautomeric forms may be relevant to the attainment of the optimalchemical reactivity and biological activity of a compound of interest.

It is also to be understood that compounds that have the same molecularformula but differ in the nature or sequence of bonding of their atomsor the arrangement of their atoms in space are termed “isomers”. Isomersthat differ in the arrangement of their atoms in space are termed“stereoisomers”.

Stereoisomers that are not mirror images of one another are termed“diastereomers” and those that are non-superimposable mirror images ofeach other are termed “enantiomers”. When a compound has an asymmetriccenter, for example, it is bonded to four different groups, a pair ofenantiomers is possible. An enantiomer can be characterized by theabsolute configuration of its asymmetric center and is described by theR- and S-sequencing rules of Cahn and Prelog, or by the manner in whichthe molecule rotates the plane of polarized light and designated asdextrorotatory or levorotatory (i.e., as (+) or (−)-isomersrespectively). A chiral compound can exist as either individualenantiomer or as a mixture thereof. A mixture containing equalproportions of the enantiomers is called a “racemic mixture”.

A “subject” to which administration is contemplated includes, but is notlimited to, humans (i.e., a male or female of any age group, e.g., apediatric subject (e.g., infant, child, adolescent) or adult subject(e.g., young adult, middleaged adult, or senior adult)) and/or othernonhuman animals, for example, mammals (e.g., primates (e.g., cynomolgusmonkeys, rhesus monkeys); commercially relevant mammals such as cattle,pigs, horses, sheep, goats, cats, and/or dogs) and birds (e.g.,commercially relevant birds such as chickens, ducks, geese, and/orturkeys). In certain embodiments, the animal is a mammal. The animal maybe a male or female and at any stage of development. A nonhuman animalmay be a transgenic animal.

The terms “administer,” “administering,” or “administration,” as usedherein refers to implanting, absorbing, ingesting, injecting, inhaling,or otherwise introducing an inventive compound, or a pharmaceuticalcomposition thereof.

As used herein, the terms “treatment,” “treat,” and “treating” refer toreversing, alleviating, delaying the onset of, or inhibiting theprogress of a “pathological condition” (e.g., a disease, disorder, orcondition, or one or more signs or symptoms thereof) described herein.In some embodiments, “treatment,” “treat,” and “treating” require thatsigns or symptoms of the disease disorder or condition have developed orhave been observed. In other embodiments, treatment may be administeredin the absence of signs or symptoms of the disease or condition. Forexample, treatment may be administered to a susceptible individual priorto the onset of symptoms (e.g., in light of a history of symptoms and/orin light of genetic or other susceptibility factors). Treatment may alsobe continued after symptoms have resolved, for example, to delay orprevent recurrence.

As used herein, the terms “condition,” “disease,” and “disorder” areused interchangeably.

An “effective amount” of a compound of Formula (I) refers to an amountsufficient to elicit the desired biological response, i.e., treating thecondition. As will be appreciated by those of ordinary skill in thisart, the effective amount of a compound of Formula (I) may varydepending on such factors as the desired biological endpoint, thepharmacokinetics of the compound, the condition being treated, the modeof administration, and the age and health of the subject. An effectiveamount encompasses therapeutic and prophylactic treatment. For example,in treating cancer, an effective amount of an inventive compound mayreduce the tumor burden or stop the growth or spread of a tumor.

A “therapeutically effective amount” of a compound of Formula (I) is anamount sufficient to provide a therapeutic benefit in the treatment of acondition or to delay or minimize one or more symptoms associated withthe condition. In some embodiments, a therapeutically effective amountis an amount sufficient to provide a therapeutic benefit in thetreatment of a condition or to minimize one or more symptoms associatedwith the condition. A therapeutically effective amount of a compoundmeans an amount of therapeutic agent, alone or in combination with othertherapies, which provides a therapeutic benefit in the treatment of thecondition. The term “therapeutically effective amount” can encompass anamount that improves overall therapy, reduces or avoids symptoms orcauses of the condition, or enhances the therapeutic efficacy of anothertherapeutic agent.

A “prophylactically effective amount” of a compound of Formula (I) is anamount sufficient to prevent a condition, or one or more symptomsassociated with the condition or prevent its recurrence. Aprophylactically effective amount of a compound means an amount of atherapeutic agent, alone or in combination with other agents, whichprovides a prophylactic benefit in the prevention of the condition. Theterm “prophylactically effective amount” can encompass an amount thatimproves overall prophylaxis or enhances the prophylactic efficacy ofanother prophylactic agent.

A “proliferative disease” refers to a disease that occurs due toabnormal growth or extension by the multiplication of cells (Walker,Cambridge Dictionary of Biology; Cambridge University Press: Cambridge,UK, 1990). A proliferative disease may be associated with: 1) thepathological proliferation of normally quiescent cells; 2) thepathological migration of cells from their normal location (e.g.,metastasis of neoplastic cells); 3) the pathological expression ofproteolytic enzymes such as the matrix metalloproteinases (e.g.,collagenases, gelatinases, and elastases); or 4) the pathologicalangiogenesis as in proliferative retinopathy and tumor metastasis.Exemplary proliferative diseases include cancers (i.e., “malignantneoplasms”), benign neoplasms, angiogenesis, inflammatory diseases,autoinflammatory diseases, and autoimmune diseases.

The terms “neoplasm” and “tumor” are used herein interchangeably andrefer to an abnormal mass of tissue wherein the growth of the masssurpasses and is not coordinated with the growth of a normal tissue. Aneoplasm or tumor may be “benign” or “malignant,” depending on thefollowing characteristics: degree of cellular differentiation (includingmorphology and functionality), rate of growth, local invasion, andmetastasis. A “benign neoplasm” is generally well differentiated, hascharacteristically slower growth than a malignant neoplasm, and remainslocalized to the site of origin. In addition, a benign neoplasm does nothave the capacity to infiltrate, invade, or metastasize to distantsites. Exemplary benign neoplasms include, but are not limited to,lipoma, chondroma, adenomas, acrochordon, senile angiomas, seborrheickeratoses, lentigos, and sebaceous hyperplasias. In some cases, certain“benign” tumors may later give rise to malignant neoplasms, which mayresult from additional genetic changes in a subpopulation of the tumor'sneoplastic cells, and these tumors are referred to as “pre-malignantneoplasms.” An exemplary pre-malignant neoplasm is a teratoma. Incontrast, a “malignant neoplasm” is generally poorly differentiated(anaplasia) and has characteristically rapid growth accompanied byprogressive infiltration, invasion, and destruction of the surroundingtissue. Furthermore, a malignant neoplasm generally has the capacity tometastasize to distant sites.

As used herein, the term “cancer” refers to a malignant neoplasm(Stedman's Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins:Philadelphia, 1990). Exemplary cancers include, but are not limited to,acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal cancer;angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma,hemangiosarcoma); appendix cancer; benign monoclonal gammopathy; biliarycancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g.,adenocarcinoma of the breast, papillary carcinoma of the breast, mammarycancer, medullary carcinoma of the breast); brain cancer (e.g.,meningioma, glioblastomas, glioma (e.g., astrocytoma,oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid tumor;cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma;chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer,rectal cancer, colorectal adenocarcinoma); connective tissue cancer;epithelial carcinoma; ependymoma; endothelio sarcoma (e.g., Kaposi'ssarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer(e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g.,adenocarcinoma of the esophagus, Barrett's adenocarcinoma); Ewing'ssarcoma; eye cancer (e.g., intraocular melanoma, retinoblastoma);familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g.,stomach adenocarcinoma); gastrointestinal stromal tumor (GIST); germcell cancer; head and neck cancer (e.g., head and neck squamous cellcarcinoma, oral cancer (e.g., oral squamous cell carcinoma), throatcancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngealcancer, oropharyngeal cancer)); hematopoietic cancers (e.g., leukemiasuch as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL),acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronicmyelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chroniclymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)); lymphomasuch as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) andnon-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large celllymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicularlymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma(CLL/SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas(e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodalmarginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma),primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacyticlymphoma (i.e., Waldenström's macroglobulinemia), hairy cell leukemia(HCL), immunoblastic large cell lymphoma, precursor B-lymphoblasticlymphoma and primary central nervous system (CNS) lymphoma; and T-cellNHL such as precursor T-lymphoblastic lymphoma/leukemia, peripheralT-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g.,mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma,extranodal natural killer T-cell lymphoma, enteropathy type T-celllymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplasticlarge cell lymphoma); a mixture of one or more leukemia/lymphoma asdescribed above; and multiple myeloma (MM)), heavy chain disease (e.g.,alpha chain disease, gamma chain disease, mu chain disease);hemangioblastoma; hypopharynx cancer; inflammatory myofibroblastictumors; immunocytic amyloidosis; kidney cancer (e.g., nephroblastomaa.k.a. Wilms' tumor, renal cell carcinoma); liver cancer (e.g.,hepatocellular cancer (HCC), malignant hepatoma); lung cancer (e.g.,bronchogenic carcinoma, small cell lung cancer (SCLC), non-small celllung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS);mastocytosis (e.g., systemic mastocytosis); muscle cancer;myelodysplastic syndrome (MDS); mesothelioma; myeloproliferativedisorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis(ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF),chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML),chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES));neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or type2, schwannomatosis); neuroendocrine cancer (e.g., gastroenteropancreaticneuroendocrine tumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g.,bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarianembryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma;pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductalpapillary mucinous neoplasm (IPMN), Islet cell tumors); penile cancer(e.g., Paget's disease of the penis and scrotum); pinealoma; primitiveneuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplasticsyndromes; intraepithelial neoplasms; prostate cancer (e.g., prostateadenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer;skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA),melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g.,appendix cancer); soft tissue sarcoma (e.g., malignant fibroushistiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor(MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous glandcarcinoma; small intestine cancer; sweat gland carcinoma; synovioma;testicular cancer (e.g., seminoma, testicular embryonal carcinoma);thyroid cancer (e.g., papillary carcinoma of the thyroid, papillarythyroid carcinoma (PTC), medullary thyroid cancer); urethral cancer;vaginal cancer; and vulvar cancer (e.g., Paget's disease of the vulva).

The term “angiogenesis” refers to the formation and the growth of newblood vessels. Normal angiogenesis occurs in the healthy body of asubject for healing wounds and for restoring blood flow to tissues afterinjury. The healthy body controls angiogenesis through a number ofmeans, e.g., angiogenesis-stimulating growth factors and angiogenesisinhibitors. Many disease states, such as cancer, diabetic blindness,age-related macular degeneration, rheumatoid arthritis, and psoriasis,are characterized by abnormal (i.e., increased or excessive)angiogenesis. Abnormal angiogenesis refers to angiogenesis greater thanthat in a normal body, especially angiogenesis in an adult not relatedto normal angiogenesis (e.g., menstruation or wound healing). Abnormalangiogenesis can provide new blood vessels that feed diseased tissuesand/or destroy normal tissues, and in the case of cancer, the newvessels can allow tumor cells to escape into the circulation and lodgein other organs (tumor metastases).

As used herein, an “inflammatory disease” refers to a disease caused by,resulting from, or resulting in inflammation. The term “inflammatorydisease” may also refer to a dysregulated inflammatory reaction thatcauses an exaggerated response by macrophages, granulocytes, and/orT-lymphocytes leading to abnormal tissue damage and/or cell death. Aninflammatory disease can be either an acute or chronic inflammatorycondition and can result from infections or non-infectious causesInflammatory diseases include, without limitation, atherosclerosis,arteriosclerosis, autoimmune disorders, multiple sclerosis, systemiclupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis,degenerative arthritis, tendonitis, bursitis, psoriasis, cysticfibrosis, arthrosteitis, rheumatoid arthritis, inflammatory arthritis,Sjogren's syndrome, giant cell arteritis, progressive systemic sclerosis(scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis,pemphigus, pemphigoid, diabetes (e.g., Type I), myasthenia gravis,Hashimoto's thyroiditis, Graves' disease, Goodpasture's disease, mixedconnective tissue disease, sclerosing cholangitis, inflammatory boweldisease, Crohn's disease, ulcerative colitis, pernicious anemia,inflammatory dermatoses, usual interstitial pneumonitis (UIP),asbestosis, silicosis, bronchiectasis, berylliosis, talcosis,pneumoconiosis, sarcoidosis, desquamative interstitial pneumonia,lymphoid interstitial pneumonia, giant cell interstitial pneumonia,cellular interstitial pneumonia, extrinsic allergic alveolitis,Wegener's granulomatosis and related forms of angiitis (temporalarteritis and polyarteritis nodosa), inflammatory dermatoses, hepatitis,delayed-type hypersensitivity reactions (e.g., poison ivy dermatitis),pneumonia, respiratory tract inflammation, Adult Respiratory DistressSyndrome (ARDS), encephalitis, immediate hypersensitivity reactions,asthma, hayfever, allergies, acute anaphylaxis, rheumatic fever,glomerulonephritis, pyelonephritis, cellulitis, cystitis, chroniccholecystitis, ischemia (ischemic injury), reperfusion injury, allograftrejection, host-versus-graft rejection, appendicitis, arteritis,blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis,chorioamnionitis, conjunctivitis, dacryoadenitis, dermatomyositis,endocarditis, endometritis, enteritis, enterocolitis, epicondylitis,epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis,gingivitis, ileitis, iritis, laryngitis, myelitis, myocarditis,nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis,pancreatitis, parotitis, pericarditis, pharyngitis, pleuritis,phlebitis, pneumonitis, proctitis, prostatitis, rhinitis, salpingitis,sinusitis, stomatitis, synovitis, testitis, tonsillitis, urethritis,urocystitis, uveitis, vaginitis, vasculitis, vulvitis, vulvovaginitis,angitis, chronic bronchitis, osteomyelitis, optic neuritis, temporalarteritis, transverse myelitis, necrotizing fasciitis, and necrotizingenterocolitis.

As used herein, an “autoimmune disease” refers to a disease arising froman inappropriate immune response of the body of a subject againstsubstances and tissues normally present in the body. In other words, theimmune system mistakes some part of the body as a pathogen and attacksits own cells. This may be restricted to certain organs (e.g., inautoimmune thyroiditis) or involve a particular tissue in differentplaces (e.g., Goodpasture's disease which may affect the basementmembrane in both the lung and kidney). The treatment of autoimmunediseases is typically with immunosuppression, e.g., medications whichdecrease the immune response. Exemplary autoimmune diseases include, butare not limited to, glomerulonephritis, Goodpasture's syndrome,necrotizing vasculitis, lymphadenitis, peri-arteritis nodosa, systemiclupus erythematosis, rheumatoid, arthritis, psoriatic arthritis,systemic lupus erythematosis, psoriasis, ulcerative colitis, systemicsclerosis, dermatomyositis/polymyositis, anti-phospholipid antibodysyndrome, scleroderma, pemphigus vulgaris, ANCA-associated vasculitis(e.g., Wegener's granulomatosis, microscopic polyangiitis), uveitis,Sjogren's syndrome, Crohn's disease, Reiter's syndrome, ankylosingspondylitis, Lyme arthritis, Guillain-Barré syndrome, Hashimoto'sthyroiditis, and cardiomyopathy.

The term “autoinflammatory disease” refers to a category of diseasesthat are similar but different from autoimmune diseases.Autoinflammatory and autoimmune diseases share common characteristics inthat both groups of disorders result from the immune system attacking asubject's own tissues and result in increased inflammation. Inautoinflammatory diseases, a subject's innate immune system causesinflammation for unknown reasons. The innate immune system reacts eventhough it has never encountered autoantibodies or antigens in thesubject. Autoinflammatory disorders are characterized by intenseepisodes of inflammation that result in such symptoms as fever, rash, orjoint swelling. These diseases also carry the risk of amyloidosis, apotentially fatal buildup of a blood protein in vital organs.Autoinflammatory diseases include, but are not limited to, familialMediterranean fever (FMF), neonatal onset multisystem inflammatorydisease (NOMID), tumor necrosis factor (TNF) receptor-associatedperiodic syndrome (TRAPS), deficiency of the interleukin-1 receptorantagonist (DIRA), and Behçet's disease.

The term “biological sample” refers to any sample including tissuesamples (such as tissue sections and needle biopsies of a tissue); cellsamples (e.g., cytological smears (such as Pap or blood smears) orsamples of cells obtained by microdissection); samples of wholeorganisms (such as samples of yeasts or bacteria); or cell fractions,fragments or organelles (such as obtained by lysing cells and separatingthe components thereof by centrifugation or otherwise). Other examplesof biological samples include blood, serum, urine, semen, fecal matter,cerebrospinal fluid, interstitial fluid, mucus, tears, sweat, pus,biopsied tissue (e.g., obtained by a surgical biopsy or needle biopsy),nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccalswabs), or any material containing biomolecules that is derived from afirst biological sample. Biological samples also include thosebiological samples that are transgenic, such as transgenic oocyte, spermcell, blastocyst, embryo, fetus, donor cell, or cell nucleus.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION Compounds

In one embodiment of the present invention, provided are compounds ofFormula (I): compound having the structural formula I:

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, orstereoisomer thereof, wherein:

ring A is an optionally substituted heteroaryl ring of any one of theFormulae (i-1)-(i-6):

wherein:

each instance of V¹, V², V³, V⁴, V⁵, V⁶, V⁷, V⁸, V⁹, V¹⁰, V¹¹, V¹², V¹³,V¹⁴ and V¹⁵ is independently O, S, N, N(R^(A1)), C, or C(R^(A2));

each instance of R^(A1) is independently selected from hydrogen,deuterium, optionally substituted acyl, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, and optionally substituted heteroaryl;

each instance of R^(A2) is independently selected from hydrogen,deuterium, halogen, —CN, optionally substituted acyl, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, —OR^(A2a), —N(R^(A2a))₂, and —SR^(A2a), whereineach occurrence of R^(A2a) is independently selected from hydrogen,optionally substituted acyl, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, and optionally substituted heteroaryl, or

any two R^(A1), any two R^(A2), or one R^(A1) and one R^(A2) are joinedto form an optionally substituted carbocyclic, optionally substitutedheterocyclic, optionally substituted aryl, or optionally substitutedheteroaryl ring;

each X is independently selected from N and CH, wherein at least one Xis N;

W is selected from N and C(R^(1a));

each of R^(1a), if present, and R^(1b) is independently selected fromhydrogen, deuterium, halogen, optionally substituted acyl, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, —CN, —OR^(B1a), —N(R^(B1a))₂, and —SR^(B1a),wherein each occurrence of R^(B1a) is independently selected fromhydrogen, optionally substituted acyl, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, and optionally substituted heteroaryl, or

R^(1a) and R^(1b) are joined to form an optionally substitutedcarbocyclic, optionally substituted heterocyclic, optionally substitutedaryl, or optionally substituted heteroaryl ring;

R² is an optionally substituted C₁-C₄ alkylene or an optionallysubstituted C₂-C₄ alkenylene or alkynylene, wherein one or moremethylene units of the alkylene, alkenylene or alkynylene are optionallyand independently replaced with —O—, —S—, or —N(R⁷)—;

R³ is selected from a bond, an optionally substituted C₁-C₄ alkylene,and an optionally substituted C₂-C₄ alkenylene or alkynylene, whereinone or more methylene units of the alkylene, alkenylene or alkynylene isoptionally and independently replaced with —O—, —S—, —N(R⁷)—, or—S(O)₂—;

R⁴ is selected from —C₁-C₈ alkyl, —O—C₁-C₈ alkyl, —NH₂, —NH(C₁-C₈alkyl), and —N(C₁-C₈ alkyl)₂, wherein each alkyl in R⁴ is optionally andindependently substituted.

each R⁵, if present, is independently selected from deuterium, halogen,optionally substituted acyl, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, —OR^(D1),—N(R^(D1))₂, and —SR^(D1), wherein each occurrence of R^(D1) isindependently selected from hydrogen, optionally substituted acyl,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, and optionally substituted aryl, optionallysubstituted heteroaryl;

each R⁶, if present, is independently selected from the group consistingof deuterium, halogen, optionally substituted acyl, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, ═O, —CN, —OR^(C1), —N(R^(C1))₂, and —SR^(C1),wherein each occurrence of R^(C1) is independently selected from thegroup consisting of hydrogen, optionally substituted acyl, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, a nitrogen protecting group when attached to anitrogen atom, an oxygen protecting group when attached to an oxygenatom, and a sulfur protecting group when attached to a sulfur atom, ortwo R^(C1) groups are joined to form an optionally substitutedheterocyclic ring; or

two R⁶ are taken together to form a first 5-7 membered, optionallysubstituted, heterocyclyl or carbocyclyl ring fused to the ring to whichthe R⁶ are bound, wherein two substituents on the substitutedheterocyclyl or carbocyclyl ring, or one substituent on the substitutedheterocyclyl or carbocyclyl ring and a third R⁶ may be taken togetherwith the atoms to which they are bound to form a second optionallysubstituted, heterocyclyl or carbocyclyl ring fused to the ring to thefirst optionally substituted, heterocyclyl or carbocyclyl ring and/orthe ring to which the third R⁶ is bound;

each R⁷ is independently selected from hydrogen, and optionallysubstituted —C₁-C₆ alkyl;

n is 0, 1, 2, 3, 4, 5 or 6; and

p is 0, 1, 2 or 3.

In certain embodiments, the compound is other than

and stereoisomers and enantiomers thereof.

In certain embodiments, no more than three of V¹, V², V³, V⁴, V⁵, V⁶,V⁷, V⁸, and V⁹ are each independently selected from the group consistingof O, S, N, and N(R^(A1)).

In certain embodiments, one of V¹⁰, V¹¹, V¹², V¹³, V¹⁴ and V¹⁵ is N andthe others of V¹⁰, V¹¹, V¹², V¹³, V¹⁴ and V¹⁵ are independentlyC(R^(A2)).

In certain embodiments, one or two of V¹, V², V³, V⁴, V⁵, V⁶, V⁷, V⁸,and V⁹ are each independently selected from the group consisting of Nand N(R^(A1)); each of V¹, V², V³, V⁴, V⁵, V⁶, and V⁷ that is notN(R^(A1)) is independently C(R^(A2)); and each V⁸ and V⁹ that is not Nis C. In one aspect of these embodiments, ring A is selected from

In certain embodiments of ring A, each R^(A1) is independently selectedfrom hydrogen, or C₁₋₆ alkyl. In certain embodiments, all instances ofR^(A1) are hydrogen.

In certain embodiments, each R^(A2) is independently selected fromhydrogen, halogen, and optionally substituted C₁-C₆ alkyl. In one aspectof these embodiments, all instances of R^(A2) are hydrogen.

In certain embodiments, ring A is selected from:

In certain embodiments, ring A is additionally selected from

In certain embodiments, each X is N.

In certain embodiments, W is N.

In other embodiments, W is C(R^(1a)).

In certain embodiments, R^(1a) is selected from selected from hydrogen,halo, —OH, —C₁-C₃ alkyl, halo-substituted —C₁-C₃ alkyl, —O—C₁-C₃ alkyl,halo-substituted —O—C₁-C₃ alkyl, —CN, —NH₂, —NH(C₁-C₃ alkyl), —N(C₁-C₃alkyl)₂, and C₃-C₆ cycloalkyl. In one aspect of these embodiments,R^(1a) selected from hydrogen, halo, —CN and C₃-C₆ cycloalkyl. In analternate aspect of these embodiments, R^(1a) selected from hydrogen,halo, —CN, halo-substituted —C₁-C₃ alkyl and C₃-C₆ cycloalkyl. In aneven more specific aspect of these embodiments, R^(1a) is selected fromhydrogen, chloro, fluoro, —CN and cyclopropyl. In another even morespecific aspect of these embodiments, R^(1a) is selected from hydrogen,chloro, fluoro, —CN, —CF₃ and cyclopropyl cyclopropyl.

In certain embodiments, R^(1b) is selected from selected from hydrogen,halo, —OH, —C₁-C₃ alkyl, halo-substituted —C₁-C₃ alkyl, —O—C₁-C₃ alkyl,halo-substituted —O—C₁-C₃ alkyl, —CN, —NH₂, —NH(C₁-C₃ alkyl), and—N(C₁-C₃ alkyl)₂. In one aspect of these embodiments, R^(1b) ishydrogen.

In certain embodiments, R² is selected from —NH—; —N(C₁-C₃ alkyl)-;—NH—CH₂—*; and C₁-C₂ alkylene optionally substituted with 1 to 4substituents independently selected from halo, —OH, —C₁-C₃ alkyl,halo-substituted —C₁-C₃ alkyl, —O—C₁-C₃ alkyl, halo-substituted —O—C₁-C₃alkyl, —CN, —NH₂, —NH(C₁-C₃ alkyl), —N(C₁-C₃ alkyl)₂, wherein “*”represents a portion of R² bound to a cyclohexyl ring. In a morespecific aspect of these embodiments, R² is —NH—.

In certain embodiments, R³ is attached meta to R², e.g., a compound ofFormula (Ia):

In certain embodiments, R³ is selected from †—NH—C(O)—, †—C(O)—NH—,†—NH—S(O)₂—, †—NH—CH(CF₃)—, and —N(CH₃)—CH₂—, wherein “t†” represents aportion of R³ bound to a cyclohexyl ring.

In some embodiments, R⁴ is selected from hydrogen, —(C₁-C₄ alkyl),—C(O)—(C₁-C₄ alkylene)-NH₂, —(C₁-C₄ alkylene)-NH₂, —NH₂, —NH—C(O)—(C₁-C₄alkylene)-NH₂, —NH—C(O)—(C₁-C₄ alkylene)-NH—(C₁-C₄ alkyl),—NH—C(O)—(C₁-C₄ alkylene)-N—(C₁-C₄ alkyl)₂, —NH—C(O)—C(O)—(C₀-C₄alkylene)-NH₂, —NH—C(O)—C(O)—(C₀-C₄ alkylene)-NH(C₁-C₄ alkyl),—NH—C(O)—C(O)—(C₀-C₄ alkylene)-N(C₁-C₄ alkyl)₂, and —NH—C(O)—(C₁-C₄alkyl). In one aspect of these embodiments, R⁴ is selected from —NH₂,—NH—C(O)—(CH₂)₃—N(CH₃)₂, —NH—C(O)—CH₂—CH(OH)—CH₂—N(CH₃)₂, —NH—CH₃, and—NH—C(O)—C(O)—NH₂.

In some embodiments, R⁵ is absent (i.e., p=0).

In some embodiments, p=1 or 2, and each R⁵ is independently selectedfrom halo and saturated heterocyclyl. In a more specific aspect of theseembodiments, each R⁵ is independently selected from fluoro, chloro andmorpholin-4-yl.

In some embodiments, R⁶ is absent (i.e., n=0).

In some embodiments, n=1 or 2 and each R⁶ is independently selected from—OH, halo, and C₁-C₃ alkyl, or two or three R⁶ bound to separate carbonatoms are taken together with the carbon atoms to form a secondcycloalkyl ring fused to the cyclohexyl ring depicted in Formula I, andwherein the second cycloalkyl ring is optionally substituted and whereina substituent on the second cycloalkyl ring is optionally taken togetherwith a third R⁶ to form a third cycloalkyl ring fused to both the secondcycloalkyl ring and the cyclohexyl ring. In a more specific aspect ofthese embodiments, each R⁶ is independently selected from —OH, fluoro,and methyl, or two or three R⁶ are taken together with the carbon atomsin the cyclohexyl ring depicted in Formula I to form:

wherein “2” represents a portion of the ring bound to R², and “3”represents a portion of the ring bound to R³.

In certain embodiments, a compound of Formula (I) has the structure ofFormula (Ib):

wherein:

ring A is selected from

R^(1a) is selected from hydrogen, chloro, fluoro, —CN and cyclopropyl;

R³ is selected from †—NH—C(O)—, †—C(O)—NH—, †—NH—S(O)₂—, †—NH—CH(CF₃)—,and —N(CH₃)—CH₂—, wherein “†” represents a portion of R³ bound to acyclohexyl ring;

R⁴ is selected from —NH₂, —NH—C(O)—(CH₂)₃—N(CH₃)₂, and—NH—C(O)—C(O)—NH₂;

R⁵ is absent, or each R⁵ is independently selected from fluoro andmorpholin-4-yl;

R⁶ is absent, or each R⁶ is independently selected from —OH, halo, andC₁-C₃ alkyl; or

two or three R⁶ bound to separate carbon atoms are taken together withthe carbon atoms to form:

wherein “2” represents a portion of the ring bound to R², and “3”represents a portion of the ring bound to R³.

In some embodiments of Formula Ib, ring A is additionally selected from

In some embodiments of Formula Ib, R⁴ is additionally selected from—NH—C(O)—CH₂—CH(OH)—CH₂—N(CH₃)₂, and —NH—CH₃.

In some embodiments of Formula Ib, R⁵ is additionally selected fromchloro.

Although, as indicated above, various embodiments and aspects thereoffor a variable in Formula (I), (Ia), or (M) may be selected from a groupof chemical moieties, the invention also encompasses as furtherembodiments and aspects thereof situations where such variable is: a)selected from any subset of chemical moieties in such a group; and b)any single member of such a group.

Although various embodiments and aspects thereof are set forth (orimplied, as discussed in the preceding paragraph) individually for eachvariable in Formula (I), (Ia), or (n) above, the invention encompassesall possible combinations of the different embodiments and aspects foreach of the variables in Formula (I), (Ia), or (Ib).

In certain embodiments, the compound of Formula (I) is selected from thegroup consisting of any one of the compounds in the table of FIGS. 1A-1Cand pharmaceutically acceptable salts, solvates, hydrates, tautomers,stereoisomers, and isotopically labeled derivatives thereof.

Pharmaceutical Compositions, Kits, and Administration

The present invention provides pharmaceutical compositions comprising acompound of Formula (I), (Ia), or (Ib), e.g., a compound of Formula (I),(Ia), or (Ib), or a pharmaceutically acceptable salt, solvate, hydrate,tautomer, stereoisomer, or isotopically labeled derivative thereof, asdescribed herein, and optionally a pharmaceutically acceptableexcipient. In certain embodiments, the pharmaceutical composition of theinvention comprises a compound of Formula (I), (Ia), or (Ib), or apharmaceutically acceptable salt thereof, and optionally apharmaceutically acceptable excipient. In certain embodiments, thecompound of Formula (I), (Ia), or (Ib), or a pharmaceutically acceptablesalt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeledderivative thereof, is provided in an effective amount in thepharmaceutical composition. In certain embodiments, the effective amountis a therapeutically effective amount. In certain embodiments, theeffective amount is a prophylactically effective amount.

Pharmaceutical compositions described herein can be prepared by anymethod known in the art of pharmacology. In general, such preparatorymethods include the steps of bringing the compound of Formula (I), (Ia),or (Ib) (the “active ingredient”) into association with a carrier and/orone or more other accessory ingredients, and then, if necessary and/ordesirable, shaping and/or packaging the product into a desired single-or multi-dose unit.

Pharmaceutical compositions can be prepared, packaged, and/or sold inbulk, as a single unit dose, and/or as a plurality of single unit doses.As used herein, a “unit dose” is a discrete amount of the pharmaceuticalcomposition comprising a predetermined amount of the active ingredient.The amount of the active ingredient is generally equal to the dosage ofthe active ingredient which would be administered to a subject and/or aconvenient fraction of such a dosage such as, for example, one-half orone-third of such a dosage.

Relative amounts of the active ingredient, the pharmaceuticallyacceptable excipient, and/or any additional ingredients in apharmaceutical composition of the invention will vary, depending uponthe identity, size, and/or condition of the subject treated and furtherdepending upon the route by which the composition is to be administered.By way of example, the composition may comprise between 0.1% and 100%(w/w) active ingredient.

The term “pharmaceutically acceptable excipient” refers to a non-toxiccarrier, adjuvant, diluent, or vehicle that does not destroy thepharmacological activity of the compound with which it is formulated.Pharmaceutically acceptable excipients useful in the manufacture of thepharmaceutical compositions of the invention are any of those that arewell known in the art of pharmaceutical formulation and include inertdiluents, dispersing and/or granulating agents, surface active agentsand/or emulsifiers, disintegrating agents, binding agents,preservatives, buffering agents, lubricating agents, and/or oils.Pharmaceutically acceptable excipients useful in the manufacture of thepharmaceutical compositions of the invention include, but are notlimited to, ion exchangers, alumina, aluminum stearate, lecithin, serumproteins, such as human serum albumin, buffer substances such asphosphates, glycine, sorbic acid, potassium sorbate, partial glyceridemixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat.

Compositions of the present invention may be administered orally,parenterally (Including subcutaneous, intramuscular, intravenous andintradermal), by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. In some embodiments,provided compounds or compositions are administrable intravenouslyand/or orally.

The term “parenteral” as used herein includes subcutaneous, intravenous,intramuscular, intraocular, intravitreal, intra-articular,intra-synovial, intrasternal, intrathecal, intrahepatic, intraperitonealintralesional and intracranial injection or infusion techniques.Preferably, the compositions are administered orally, subcutaneously,intraperitoneally or intravenously. Sterile injectable forms of thecompositions of this invention may be aqueous or oleaginous suspension.These suspensions may be formulated according to techniques known in theart using suitable dispersing or wetting agents and suspending agents.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium.

Pharmaceutically acceptable compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers commonly used include lactose andcorn starch. Lubricating agents, such as magnesium stearate, are alsotypically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added. In some embodiments, aprovided oral formulation is formulated for immediate release orsustained/delayed release. In some embodiments, the composition issuitable for buccal or sublingual administration, including tablets,lozenges and pastilles. A provided compound can also be inmicro-encapsulated form.

Alternatively, pharmaceutically acceptable compositions of thisinvention may be administered in the form of suppositories for rectaladministration. Pharmaceutically acceptable compositions of thisinvention may also be administered topically, especially when the targetof treatment includes areas or organs readily accessible by topicalapplication, including diseases of the eye, the skin, or the lowerintestinal tract. Suitable topical formulations are readily prepared foreach of these areas or organs.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For ophthalmic use, provided pharmaceutically acceptable compositionsmay be formulated as micronized suspensions or in an ointment such aspetrolatum.

Pharmaceutically acceptable compositions of this invention may also beadministered by nasal aerosol or inhalation.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This can be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Although the descriptions of pharmaceutical compositions provided hereinare principally directed to pharmaceutical compositions which aresuitable for administration to humans, it will be understood by theskilled artisan that such compositions are generally suitable foradministration to animals of all sorts. Modification of pharmaceuticalcompositions suitable for administration to humans in order to renderthe compositions suitable for administration to various animals is wellunderstood, and the ordinarily skilled veterinary pharmacologist candesign and/or perform such modification with ordinary experimentation.

Compounds provided herein are typically formulated in dosage unit form,e.g., single unit dosage form, for ease of administration and uniformityof dosage. It will be understood, however, that the total daily usage ofthe compositions of the present invention will be decided by theattending physician within the scope of sound medical judgment. Thespecific therapeutically effective dose level for any particular subjector organism will depend upon a variety of factors including the diseasebeing treated and the severity of the disorder; the activity of thespecific active ingredient employed; the specific composition employed;the age, body weight, general health, sex and diet of the subject; thetime of administration, route of administration, and rate of excretionof the specific active ingredient employed; the duration of thetreatment; drugs used in combination or coincidental with the specificactive ingredient employed; and like factors well known in the medicalarts.

The exact amount of a compound required to achieve an effective amountwill vary from subject to subject, depending, for example, on species,age, and general condition of a subject, severity of the side effects ordisorder, identity of the particular compound(s), mode ofadministration, and the like. The desired dosage can be delivered threetimes a day, two times a day, once a day, every other day, every thirdday, every week, every two weeks, every three weeks, or every fourweeks. In certain embodiments, the desired dosage can be delivered usingmultiple administrations (e.g., two, three, four, five, six, seven,eight, nine, ten, eleven, twelve, thirteen, fourteen, or moreadministrations).

In certain embodiments, an effective amount of a compound foradministration one or more times a day to a 70 kg adult human maycomprise about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg,about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosageform.

In certain embodiments, the compounds of Formula (I), (Ia), or (Ib) maybe at dosage levels sufficient to deliver from about 0.001 mg/kg toabout 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, preferablyfrom about 0.1 mg/kg to about 40 mg/kg, preferably from about 0.5 mg/kgto about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about0.1 mg/kg to about 10 mg/kg, and more preferably from about 1 mg/kg toabout 25 mg/kg, of subject body weight per day, one or more times a day,to obtain the desired therapeutic effect.

It will be appreciated that dose ranges as described herein provideguidance for the administration of provided pharmaceutical compositionsto an adult. The amount to be administered to, for example, a child oran adolescent can be determined by a medical practitioner or personskilled in the art and can be lower or the same as that administered toan adult.

It will be also appreciated that a compound or composition, as describedherein, can be administered in combination with one or more additionalpharmaceutical agents. The compounds or compositions can be administeredin combination with additional pharmaceutical agents that improve theirbioavailability, reduce and/or modify their metabolism, inhibit theirexcretion, and/or modify their distribution within the body. It willalso be appreciated that the therapy employed may achieve a desiredeffect for the same disorder, and/or it may achieve different effects.

The compound or composition can be administered concurrently with, priorto, or subsequent to, one or more additional pharmaceutical agents,which may be useful as, e.g., combination therapies. Pharmaceuticalagents include therapeutically active agents. Pharmaceutical agents alsoinclude prophylactically active agents. Each additional pharmaceuticalagent may be administered at a dose and/or on a time schedule determinedfor that pharmaceutical agent. The additional pharmaceutical agents mayalso be administered together with each other and/or with the compoundor composition described herein in a single dose or administeredseparately in different doses. The particular combination to employ in aregimen will take into account compatibility of the inventive compoundwith the additional pharmaceutical agents and/or the desired therapeuticand/or prophylactic effect to be achieved. In general, it is expectedthat the additional pharmaceutical agents utilized in combination beutilized at levels that do not exceed the levels at which they areutilized individually. In some embodiments, the levels utilized incombination will be lower than those utilized individually.

Exemplary additional pharmaceutical agents include, but are not limitedto, anti-proliferative agents, anti-cancer agents, anti-diabetic agents,anti-inflammatory agents, immunosuppressant agents, and a pain-relievingagent. Pharmaceutical agents include small organic molecules such asdrug compounds (e.g., compounds approved by the U.S. Food and DrugAdministration as provided in the Code of Federal Regulations (CFR)),peptides, proteins, carbohydrates, monosaccharides, oligosaccharides,polysaccharides, nucleoproteins, mucoproteins, lipoproteins, syntheticpolypeptides or proteins, small molecules linked to proteins,glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides,nucleosides, oligonucleotides, antisense oligonucleotides, lipids,hormones, vitamins, and cells.

Also encompassed by the invention are kits (e.g., pharmaceutical packs).The inventive kits may be useful for preventing and/or treating aproliferative disease (e.g., cancer (e.g., leukemia, melanoma, multiplemyeloma), benign neoplasm, angiogenesis, inflammatory disease,autoinflammatory disease, or autoimmune disease). The kits provided maycomprise an inventive pharmaceutical composition or compound and acontainer (e.g., a vial, ampule, bottle, syringe, and/or dispenserpackage, or other suitable container). In some embodiments, providedkits may optionally further include a second container comprising apharmaceutical excipient for dilution or suspension of an inventivepharmaceutical composition or compound. In some embodiments, theinventive pharmaceutical composition or compound provided in thecontainer and the second container are combined to form one unit dosageform.

Thus, in one aspect, provided are kits including a first containercomprising a compound described herein, or a pharmaceutically acceptablesalt, solvate, hydrate, tautomer, stereoisomer, and isotopically labeledderivative, or a pharmaceutical composition thereof. In certainembodiments, the kit of the invention includes a first containercomprising a compound described herein, or a pharmaceutically acceptablesalt thereof, or a pharmaceutical composition thereof. In certainembodiments, the kits are useful in preventing and/or treating aproliferative disease in a subject. In certain embodiments, the kitsfurther include instructions for administering the compound, or apharmaceutically acceptable salt, solvate, hydrate, tautomer,stereoisomer, isotopically and labeled derivative thereof, or apharmaceutical composition thereof, to a subject to prevent and/or treata proliferative disease.

Methods of Treatment and Uses

The present invention also provides methods for the treatment orprevention of a proliferative disease (e.g., cancer, benign neoplasm,angiogenesis, inflammatory disease, autoinflammatory disease, orautoimmune disease) or an infectious disease (e.g., a viral disease) ina subject. Such methods comprise the step of administering to thesubject in need thereof an effective amount of a compound of Formula(I), (Ia), or (Ib), or a pharmaceutically acceptable salt, solvate,hydrate, tautomer, stereoisomer, or isotopically labeled derivativethereof, or a pharmaceutical composition thereof. In certainembodiments, the methods described herein include administering to asubject an effective amount of a compound of Formula (I), (Ia), or (Ib),or a pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition thereof.

In certain embodiments, the subject being treated is a mammal. Incertain embodiments, the subject is a human. In certain embodiments, thesubject is a domesticated animal, such as a dog, cat, cow, pig, horse,sheep, or goat. In certain embodiments, the subject is a companionanimal such as a dog or cat. In certain embodiments, the subject is alivestock animal such as a cow, pig, horse, sheep, or goat. In certainembodiments, the subject is a zoo animal. In another embodiment, thesubject is a research animal such as a rodent, dog, or non-humanprimate. In certain embodiments, the subject is a non-human transgenicanimal such as a transgenic mouse or transgenic pig.

The proliferative disease to be treated or prevented using the compoundsof Formula (I), (Ia), or (Ib) will typically be associated with aberrantactivity of CDK7. Aberrant activity of CDK7 may be an elevated and/or aninappropriate (e.g., abnormal) activity of CDK7. In certain embodiments,CDK7 is not overexpressed, and the activity of CDK7 is elevated and/orinappropriate. In certain other embodiments, CDK7 is overexpressed, andthe activity of CDK7 is elevated and/or inappropriate. The compounds ofFormula (I), (Ia), or (Ib), and pharmaceutically acceptable salts,solvates, hydrates, tautomers, stereoisomers, isotopically labeledderivatives, and compositions thereof, may inhibit the activity of CDK7and be useful in treating and/or preventing proliferative diseases.

In other embodiments, the proliferative disease to be treated orprevented using the compounds of Formula (I), (Ia), or (Ib) willtypically be associated with aberrant activity of other CDK familymembers. In some embodiments, the other CDK family members are CDK12and/or CDK13. Aberrant activity of CDK12 and/or CDK13 may be an elevatedand/or an inappropriate (e.g., abnormal) activity of CDK12 and/or CDK13.In certain embodiments, CDK12 and/or CDK13 is not overexpressed, and theactivity of CDK12 and/or CDK13 is elevated and/or inappropriate. Incertain other embodiments, CDK12 and/or CDK13 is overexpressed, and theactivity of CDK12 and/or CDK13 is elevated and/or inappropriate. Thecompounds of Formula (I), (Ia), or (Ib), and pharmaceutically acceptablesalts, solvates, hydrates, tautomers, stereoisomers, isotopicallylabeled derivatives, and compositions thereof, may inhibit the activityof CDK12 and/or CDK13 and be useful in treating and/or preventingproliferative diseases.

A proliferative disease may also be associated with inhibition ofapoptosis of a cell in a biological sample or subject. All types ofbiological samples described herein or known in the art are contemplatedas being within the scope of the invention. Inhibition of the activityof CDK7 is expected to cause cytotoxicity via induction of apoptosis.The compounds of Formula (I), (Ia), or (Ib), and pharmaceuticallyacceptable salts, solvates, hydrates, tautomers, stereoisomers,isotopically labeled derivatives, and compositions thereof, may induceapoptosis, and therefore, be useful in treating and/or preventingproliferative diseases.

In certain embodiments, the proliferative disease to be treated orprevented using the compounds of Formula (I), (Ia), or (Ib) is cancer.All types of cancers disclosed herein or known in the art arecontemplated as being within the scope of the invention. In certainembodiments, the proliferative disease is a cancer associated withdependence on BCL-2 anti-apoptotic proteins (e.g., MCL-1 and/or XIAP).In certain embodiments, the proliferative disease is a cancer associatedwith overexpression of MYC (a gene that codes for a transcriptionfactor). In certain embodiments, the proliferative disease is ahematological malignancy. In certain embodiments, the proliferativedisease is a blood cancer. In certain embodiments, the proliferativedisease is leukemia. In certain embodiments, the proliferative diseaseis chronic lymphocytic leukemia (CLL). In certain embodiments, theproliferative disease is acute lymphoblastic leukemia (ALL). In certainembodiments, the proliferative disease is T-cell acute lymphoblasticleukemia (T-ALL). In certain embodiments, the proliferative disease ischronic myelogenous leukemia (CML). In certain embodiments, theproliferative disease is acute myelogenous leukemia (AML). In certainembodiments, the proliferative disease is lymphoma. In certainembodiments, the proliferative disease is melanoma. In certainembodiments, the proliferative disease is multiple myeloma. In certainembodiments, the proliferative disease is a bone cancer. In certainembodiments, the proliferative disease is osteosarcoma. In someembodiments, the proliferative disease is Ewing's sarcoma. In someembodiments, the proliferative disease is triple-negative breast cancer(TNBC). In some embodiments, the proliferative disease is a braincancer. In some embodiments, the proliferative disease is neuroblastoma.In some embodiments, the proliferative disease is a lung cancer. In someembodiments, the proliferative disease is small cell lung cancer (SCLC).In some embodiments, the proliferative disease is large cell lungcancer. In some embodiments, the proliferative disease is a benignneoplasm. All types of benign neoplasms disclosed herein or known in theart are contemplated as being within the scope of the invention.

In some embodiments, the proliferative disease is associated withangiogenesis. All types of angiogenesis disclosed herein or known in theart are contemplated as being within the scope of the invention.

In certain embodiments, the proliferative disease is an inflammatorydisease. All types of inflammatory diseases disclosed herein or known inthe art are contemplated as being within the scope of the invention. Incertain embodiments, the inflammatory disease is rheumatoid arthritis.In some embodiments, the proliferative disease is an autoinflammatorydisease. All types of autoinflammatory diseases disclosed herein orknown in the art are contemplated as being within the scope of theinvention. In some embodiments, the proliferative disease is anautoimmune disease. All types of autoimmune diseases disclosed herein orknown in the art are contemplated as being within the scope of theinvention.

The cell described herein may be an abnormal cell. The cell may be invitro or in vivo. In certain embodiments, the cell is a proliferativecell. In certain embodiments, the cell is a blood cell. In certainembodiments, the cell is a lymphocyte. In certain embodiments, the cellis a cancer cell. In certain embodiments, the cell is a leukemia cell.In certain embodiments, the cell is a CLL cell. In certain embodiments,the cell is a melanoma cell. In certain embodiments, the cell is amultiple myeloma cell. In certain embodiments, the cell is a benignneoplastic cell. In certain embodiments, the cell is an endothelialcell. In certain embodiments, the cell is an immune cell.

In another aspect, the present invention provides methods ofdown-regulating the expression of a CDK (e.g., CDK7, CDK1, CDK2, CDK5,CDK8, CDK9, CDK12, or CDK13) in a biological sample or subject. Incertain embodiments, the present invention provides methods ofdown-regulating the expression of CDK7 in a biological sample orsubject. In another aspect, the present invention provides methods ofdown-regulating the expression of Jurkat, IRAK1, JNK1, JNK2, or MLK3 ina biological sample or subject.

In certain embodiments, the methods described herein comprise theadditional step of administering one or more additional pharmaceuticalagents in combination with the compound of Formula (I), (Ia), or (Ib), apharmaceutically acceptable salt thereof, or compositions comprisingsuch compound or pharmaceutically acceptable salt thereof. Suchadditional pharmaceutical agents include, but are not limited to,anti-proliferative agents, anti-cancer agents, anti-diabetic agents,anti-inflammatory agents, immunosuppressant agents, and a pain-relievingagent. The additional pharmaceutical agent(s) may synergisticallyaugment inhibition of CDK7, CDK12, or CDK13 induced by the inventivecompounds or compositions of this invention in the biological sample orsubject. In certain embodiments, the additional pharmaceutical agent isflavopiridol, triptolide, SNS-032 (BMS-387032), PHA-767491, PHA-793887,BS-181, (S)—CR8, (R)—CR8, or NU6140. In certain embodiments, theadditional pharmaceutical agent is an inhibitor of a mitogen-activatedprotein kinase (MAPK). In certain embodiments, the additionalpharmaceutical agent is an inhibitor of a glycogen synthase kinase 3(GSK3). In certain embodiments, the additional pharmaceutical agent isan inhibitor of an AGC kinase. In certain embodiments, the additionalpharmaceutical agent is an inhibitor of a CaM kinase. In certainembodiments, the additional pharmaceutical agent is an inhibitor of acasein kinase 1. In certain embodiments, the additional pharmaceuticalagent is an inhibitor of a STE kinase. In certain embodiments, theadditional pharmaceutical agent is an inhibitor of a tyrosine kinase.Thus, the combination of the inventive compounds or compositions and theadditional pharmaceutical agent(s) may be useful in treatingproliferative diseases resistant to a treatment using the additionalpharmaceutical agent(s) without the inventive compounds or compositions.

In yet another aspect, the present invention provides the compounds ofFormula (I), (Ia), or (Ib), and pharmaceutically acceptable salts,solvates, hydrates, tautomers, stereoisomers, isotopically labeledderivatives, and compositions thereof, for use in the treatment of aproliferative disease in a subject. In certain embodiments, provided bythe invention are the compounds described herein, and pharmaceuticallyacceptable salts and compositions thereof, for use in the treatment of aproliferative disease in a subject. In certain embodiments, provided bythe invention are the compounds described herein, and pharmaceuticallyacceptable salts and compositions thereof, for use in inhibiting cellgrowth. In certain embodiments, provided by the invention are thecompounds described herein, and pharmaceutically acceptable salts andcompositions thereof, for use in inducing apoptosis in a cell. Incertain embodiments, provided by the invention are the compoundsdescribed herein, and pharmaceutically acceptable salts and compositionsthereof, for use in inhibiting transcription.

EXAMPLES

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. The synthetic andbiological examples described in this application are offered toillustrate the compounds, pharmaceutical compositions, and methodsprovided herein and are not to be construed in any way as limiting theirscope.

The compounds provided herein can be prepared from readily availablestarting materials using modifications to the specific synthesisprotocols set forth below that would be well known to those of skill inthe art. It will be appreciated that where typical or preferred processconditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. Optimum reactionconditions may vary with the particular reactants or solvents used, butsuch conditions can be determined by those skilled in the art by routineoptimization procedures.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. The choice of asuitable protecting group for a particular functional group as well assuitable conditions for protection and deprotection are well known inthe art. For example, numerous protecting groups, and their introductionand removal, are described in Greene et al., Protecting Groups inOrganic Synthesis, Second Edition, Wiley, New York, 1991, and referencescited therein.

ABBREVIATIONS Ac acetyl ACN acetonitrile aq. aqueous atm atmospheres Boctert-butoxy carbonyl Boc₂O Di-t-butyl dicarbonate Bn Benzyl DCCN,N′-Dicyclohexylcarbodiimide DCM Dichloromethane DCE DichloroetheneDIAD Diisopropyl azodicarboxylate DIPEA N,N-Diisopropyl ethylamine DMADimethylacetamide DMF Dimethylformamide DMSO Dimethylsulfoxide DPPADiphenoxyphosphoryl azide EDTA Ethylenediamine tetraacetic acid eq(s).equivalent(s) EtOAc Ethyl acetate Et Ethyl EtOH Ethanol Et₃NTriethylamine g gram(s) h hour(s) HATU (Dimethylamino)-N,N-dimethyl(3H-[1,2,3]triazolo[4,5- b]pyridin-3- yloxy)methaniminiumhexafluorophosphate HBTU O-Benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro- phosphate Hex Hexanes HOBt1-Hydroxybenzotriazole HPLC High pressure liquid chromatography IPAIsopropanol LCMS; liquid chromatography mass LC-MS spectrometry Me-Dimethylaminosulfurtrifluoride DAST MeOH methanol mg milligram(s) minMinute(s) mL; ml milliliter(s) MS mass spectrometry mW microwave NMeN-methyl NMP N-Methyl-2-pyrrolidone NMR Nuclear magnetic resonancePd₂dba₃ Tris(dibenzylideneacetone) dipalladium(0) Ph phenyl pyr Pyridiner.t.; rt; Room temperature RT S., sat. saturated TEA Triethylamine TFATrifluoroacetic acid THF Tetrahydrofuran TLC Thin layer chromatographyX-Phos 2-Dicyclohexylphosphino-2′,4′,6′- triisopropylbiphenyl

Example 1.4-amino-N-(3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)tricyclo[3.3.1.1^(3,7)]decanyl)benzamide(Compound 100) Dibenzyltricyclo[3.3.1.1^(3,7)]decane-1,3-diyldicarbamate

A solution of tricyclo[3.3.1.1^(3,7)]decane-1,3-dicarboxylic acid (500mg, 2.230 mmol) in toluene (9 mL) was treated with Et₃N (0.68 mL, 4.91mmol) and DPPA (0.96 mL, 4.46 mmol) and heated at 110° C. for 1 h. Themixture was cooled down to 80° C. and treated with benzyl alcohol (0.580mL, 5.574 mmol) and Et₃N (0.68 mL, 4.91 mmol). The resulting mixture washeated at 80° C. for 20h. The cooled mixture was then diluted with EtOAc(50 mL) and H₂O (50 mL). The layers were separated and the aqueous layerwas extracted with EtOAc (3×50 mL). The combined organics layers werewashed with brine (50 mL), filtered and evaporated to dryness. Theresidue was purified by SiO₂ chromatography (Hex/EtOAc 0 to 70%gradient) to afford the title compound (800 mg, 1.97 mmol, 88%) as clearoil.

Tricyclo[3.3.1.1^(3,7)]decane-1,3-diamine

A degassed solution of dibenzyltricyclo[3.3.1.1^(3,7)]decane-1,3-diyldicarbamate (773 mg, 0.223 mmol)in EtOH (45 mL) was treated with 10% w/w Pd/C (356 mg). The mixture wasstirred 18h under hydrogen (1 atm) before filtration over a pad ofcelite (EtOH). The filtrate was evaporated under reduced pressure toafford the title compound (348 mg, 2.10 mmol, 94%) as a colorless oilwhich was used in the next step without further purification.

N1-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)tricyclo[3.3.1.1^(3,7)]decane-1,3-diamine

A solution of3-(2,5-dichloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole (450 mg,1.11 mmol), tricyclo[3.3.1.1^(3,7)]decane-1,3-diamine (278 mg, 1.67mmol) and DIPEA (0.29 mL, 1.67 mmol) in NMP (11 mL) was heated at 135°C. (microwave) for 75 min. The cooled mixture was diluted with EtOAc (50mL), washed with H₂O (15 mL), brine (15 mL), dried over MgSO₄, filteredand evaporated to dryness. The residue was purified by C₁₈chromatography (H₂O/ACN+0.1% HCO₂H 5 to 100% gradient) to afford thetitle compound (168 mg, 0.315 mmol, 28%) as a light orange oil.

tert-butyl4-(3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)tricyclo[3.3.1.1^(3,7)]decanylcarbamoyl)phenylcarbamate

A solution ofN1-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)tricyclo[3.3.1.1^(3,7)]decane-1,3-diamine(193 mg, 0.360 mmol) and 4-(tert-butoxycarbonylamino)benzoic acid (86mg, 0.360 mmol) in 4/1 DCM/DMF (5 mL) was treated with HBTU (274 mg,0.720 mmol) and DIPEA (0.19 mL, 1.08 mmol). The resulting mixture wasstirred 18h at rt and diluted with DCM (20 mL) and saturated NaHCO₃ (10mL). The layers were separated and the organic layer was extracted withDCM (3×10 mL). The combined organic layers were washed with brine (10mL), dried over MgSO₄, filtered, and evaporated to dryness. The residuewas purified by SiO₂ chromatography (DCM/EtOAc 0 to 50% gradient) toafford the title compound (70 mg, 0.093 mmol, 26%) as a light yellowoil.

4-amino-N-(3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)tricyclo[3.3.1.1^(3,7)]decanyl)benzamide.TFA

A solution of tert-butyl4-(3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)tricyclo[3.3.1.1^(3,7)]decanylcarbamoyl)phenylcarbamate(70 mg, 0.093 mmol) in DCM (2 mL) was treated with TFA (1.1 mL, 13.94mmol). The resulting mixture was stirred 1h at rt before beingevaporated to dryness. The residue was dried under high vacuum to affordthe title compound (71 mg, 0.093 mmol, 100%) as a light yellow oil whichwas used in the next step without further purification.

4-amino-N-(3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)tricyclo[3.3.1.1^(3,7)]decanxyl)benzamide

A solution of4-amino-N-(3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)tricyclo[3.3.1.1^(3,7)]decanyl)benzamide.TFA(47 mg, 0.072 mmol) in dioxane (1.5 mL) was treated with a 5M aqueoussolution of NaOH (0.29 mL, 1.44 mmol) and heated 70° C. for 4h. Thecooled mixture was treated with a 1M aqueous solution of HCl until pH=7,extracted with EtOAc (3×10 mL), dried over MgSO₄, filtered andevaporated under reduced pressure. The residue was purified by C₁₈chromatography (H₂O/ACN+0.1% HCO₂H 5 to 100% gradient) to afford thetitle compound (9.5 mg, 0.019 mmol, 26%) as a white solid.

Example 2.(+/−)-4-amino-N-(3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)-5-hydroxycyclohexyl)benzamide(Compound 101)(+/−)-5-(tert-butyldimethylsilyloxy)cyclohexane-1,3-diamine

A degassed solution oftert-butyl((+/−)-3,5-diazidocyclohexyloxy)dimethylsilane (300 mg, 1.01mmol) (prepared following New J. Chem., 2005, 29, 1152-1158) in MeOH (7mL) was treated with 10% Pd/C (108 mg, 0.10 mmol) and stirred 2h underhydrogen (1 atm). The resulting mixture was filtered over a pad ofcelite and the filtrate was evaporated to dryness leaving the titlecompound (227 mg, 0.930 mmol, 92%) as a beige solid which was used inthe next step without further purification.

(+/−)-5-(tert-butyldimethylsilyloxy)-N¹-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)cyclohexane-1,3-diamine

A solution of3-(2,5-dichloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole (340 mg,0.84 mmol), (+/−)-5-(tert-butyldimethylsilyloxy)cyclohexane-1,3-diamine(226 mg, 0.93 mmol) and DIPEA (161 μL, 0.93 mmol) in NMP (1.4 mL) washeated at 135° C. (microwave) for 25 min. The cooled mixture was dilutedwith EtOAc (30 mL), washed with H₂O (10 mL), brine (10 mL), dried overMgSO₄, filtered, and evaporated to dryness. The residue was purified byC₁₈ chromatography (H₂O/ACN+0.1% HCO₂H 5 to 80% gradient) to afford thetitle compound (97 mg, 0.158 mmol, 19%) as a pale yellow solid.

(+/−)-tert-butyl4-(-3-(tert-butyldimethylsilyloxy)-5-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexylcarbamoyl)phenylcarbamate

A solution of(+/−)-5-(tert-butyldimethylsilyloxy)-N¹-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)cyclohexane-1,3-diamine(97 mg, 0.16 mmol) and 4-(tert-butoxycarbonylamino)benzoic acid (38 mg,0.16 mmol) in DCM (1.1 mL) was treated with HBTU (120 mg, 0.32 mmol) andDIPEA (83 μL, 0.48 mmol). The resulting mixture was stirred 18h at rtand evaporated to dryness. The residue was purified by SiO₂chromatography (DCM/EtOAc 0 to 50% gradient) to afford the titlecompound (93 mg, 0.111 mmol, 71%) as a light yellow oil.

(+/−)-4-amino-N-(3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)-5-hydroxycyclohexyl)benzamide

A solution of (+/−)-tert-butyl4-(-3-(tert-butyldimethylsilyloxy)-5-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexylcarbamoyl)phenylcarbamate(93.0 mg, 0.112 mmol) in THF (4.5 mL) was treated with a 1M solution ofTBAF in THF (168 μL, 0.168 mmol) and stirred 2 days at rt. The resultingmixture was evaporated to dryness and the residue was purified byreverse phase chromatography (C₁₈, H₂O/ACN+0.1% HCO₂H 10 to 100%gradient) and to afford the title compound (32 mg, 0.067 mmol, 60%) as ayellow solid.

Example 3.4-amino-N-((1S,3R)-3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)benzamide(Compound 102) (1S,3R)-3-(Benzyloxycarbonylamino)cyclohexylamino2,2-dimethylpropionate

To a solution of(1R,3S)-3-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid (preparedfollowing Tetrahedron: Asymmetry 2010 (21), 864-866) (8.77 g, 36.1 mmol)was added Et₃N (5.53 mL, 39.7 mmol) and DPPA (7.7 mL, 36.1 mmol). Theresulting solution was stirred 2h at 110° C. then cooled down to 80° C.Benzyl alcohol (4.66 mL, 45.1 mmol) and triethylamine (5.53 mL, 39.7mmol) were added and the mixture was stirred 20h at 80° C. The cooledsolution was diluted with EtOAc (100 mL) and H₂O (50 mL). The layerswere separated and the aqueous layer was extracted with EtOAc (2×50 mL).The combined organics were dried (MgSO₄), filtered and evaporated todryness. The residue was purified by SiO₂ chromatography (Hex/EtOAc 1 to100% gradient), and afforded the title compound (9.89 g, 28.4 mmol, 79%)as a white solid.

tert-butyl (1S,3R)-3-aminocyclohexylcarbamate

To a degassed solution of(1S,3R)-3-(Benzyloxycarbonylamino)cyclohexylamino 2,2-dimethylpropionate(10 g, 28.4 mmol) in EtOH (473 mL) was added 10% w/w Pd/C (450 mg). Thereaction mixture was stirred 5h under H₂ (1 atm). The reaction mixturewas filtered through a pad of celite (EtOH) and the filtrate wasevaporated to dryness to afford the title compound (6.08 g, 28.4 mmol,100%) as a white solid.

tert-butyl-(1S,3R)-3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexylcarbamate

A solution of3-(2,5-dichloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole (2.91 g,7.20 mmol), tert-butyl (1S,3R)-3-aminocyclohexylcarbamate (1.24 g, 5.76mmol) and diisopropylethylamine (1.05 mL, 6.05 mmol) in NMP (14.5 mL)was heated 1.5h at 135° C. (mW). The mixture was diluted with EtOAc (200mL), washed with H₂O (50 mL), brine (50 mL), dried (MgSO₄), filtered andevaporated to dryness. The residue was purified by SiO₂ chromatography(DCM/EtOAc 0 to 30% gradient) and afforded the title compound (1.88 g,3.23 mmol, 56%) as a light yellow foam.

(1R,3S)—N¹-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)cyclohexane-1,3-diamine.HCl

To a solution of tert-butyl(1S,3R)-3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexylcarbamate(1.88 g, 3.23 mmol) in DCM (16.1 mL) was added a solution of HCl 4 N indioxane (12.11 mL, 48.44 mmol). The resulting mixture was stirred 1.5hat rt before being evaporated to dryness and afforded the title compound(1.72 g, 3.10 mmol, 96%) as a light yellow solid which was used in thenext step without further purification.

tert-butyl-4-((1S,3R)-3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexylcarbamoyl)phenylcarbamate

A solution of(1R,3S)—N¹-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)cyclohexane-1,3-diamine.HCl(840 mg, 1.62 mmol), 4-(tert-butoxycarbonylamino)benzoic acid (462 mg,1.95 mmol), HBTU (924 mg, 2.44 mmol), Et₃N (680 μL, 4.87 mmol) in DMF(8.0 mL) was stirred overnight at rt. The mixture was diluted with EtOAc(50 mL), washed with sat NaHCO₃ (10 mL), H₂O (10 mL) and brine (10 mL).The organic layer was dried over MgSO₄, filtered and concentrated underreduced pressure and afforded the title compound which was used in thenext step without further purification (1.14 g, 1.62 mmol, 100%)

4-amino-N-((1S,3R)-3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)benzamide.HCl

A solution of tert-butyl44(1S,3R)-3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexylcarbamoyl)phenylcarbamate(1.14 g, 1.62 mmol) in DCM (10 mL) was treated with a 4M solution of HClin dioxane (8.1 mL, 32.4 mmol) ans stirred 3h at rt. The resultingmixture was evaporated to dryness and afforded the title compound (948mg, 1.62 mmol, 100%) as a pale yellow solid which was used in the nextstep without further purification.

4-amino-N-((1S,3R)-3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)benzamide

A solution of4-amino-N4(1S,3R)-3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)benzamide.HCl(1.72 g, 3.10 mmol) and NaOH 5M (9.3 mL, 46.5 mmol) in dioxane (20 mL)was stirred 2.5h at 75° C. The cooled mixture was concentrated, dilutedwith DCM (100 mL) and H₂O (20 mL). The layers were separated and theaqueous layer was extracted with DCM (3×20 mL), dried over MgSO₄,filtered, evaporated to dryness and afforded the title compound (1.20 g,2.60 mmol, 84%) as a white solid.

Example 4.(1S,3R)—N-(4-aminophenyl)-3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexanecarboxamide(Compound 106) (1S,3R)-methyl3-(tert-butoxycarbonylamino)cyclohexanecarboxylate

A solution of (1R,3S)-3-(tert-butoxycarbonylamino)cyclohexanecarboxylicacid (prepared following Tetrahedron: Asymmetry 2010 (21), 864-866) (1.0g, 4.11 mmol), K₂CO₃ (474 mg, 3.43 mmol) and MeI (0.21 mL, 3.43 mmol) inDMF (8 mL) was stirred 72h at rt. The resulting mixture was diluted withH₂O (30 mL) and EtOAc (100 mL). The layers were separated and theaqueous layer was extracted with EtOAc (3×50 mL). The combined organiclayers were dried over MgSO₄, filtered, and evaporated to drynessleaving the title compound (1.35 g, 4.11 mmol, 100%) as a light orangesolid which was used in the next step without further purification.

(1S,3R)-methyl 3-aminocyclohexanecarboxylate.HCl

A solution of (1S,3R)-methyl3-(tert-butoxycarbonylamino)cyclohexanecarboxylate (1.058 g, 4.111 mmol)in DCM (20.6 mL) was treated with a 4M solution of HCl in dioxane (10.3mL, 10.3 mmol) and stirred for 16h. The mixture was concentrated todryness leaving the title compound (739 mg, 3.81 mmol, 93%) as a lightyellow solid which was used in the next step without furtherpurification.

(1S,3R)-methyl3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexanecarboxylate

A solution of3-(2,5-dichloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole (1.401 g,3.464 mmol), (1S,3R)-methyl 3-aminocyclohexanecarboxylate.HCl (639 mg,3.299 mmol) and DIPEA (1.7 mL, 9.90 mmol) in NMP (13 mL) was heated at135° C. (microwave) for 25 min. The cooled mixture was diluted withEtOAc (50 mL), washed with H₂O (15 mL), brine (15 mL), dried over MgSO₄,filtered, and evaporated to dryness. The residue was purified by SiO₂chromatography (DCM/EtOAc 0 to 10% gradient) to afford the titlecompound (900 mg, 1.71 mmol, 52%) as a white foam.

(1S,3R)-3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexanecarboxylicacid

A solution of (1S,3R)-methyl3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexanecarboxylate(200 mg, 0.38 mmol) in THF was treated with a 0.55M solution of LiOH.H₂Oin H₂O (0.8 mL, 0.4 mmol) and for three days at rt. The mixture wasdiluted with EtOAc (20 mL) and acidified with 1M HCl until the pHreached 2-3. The layers were separated and the aqueous layer wasextracted with EtOAc (3×10 mL), dried over MgSO₄, filtered andevaporated to dryness leaving the title compound (108 mg, 0.211 mmol,56%) as a white solid which was used in the next step without furtherpurification.

tert-butyl 4-((1S,3R)-3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexanecarboxamido)phenylcarbamate

A solution of(1S,3R)-3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexanecarboxylicacid (108 mg, 0.21 mmol) and tert-butyl 4-aminophenylcarbamate (44 mg,0.21 mmol) in DCM (1.4 mL) was treated with HBTU (160 mg, 0.42 mmol) andDIPEA (0.11 mL, 0.63 mmol). The resulting mixture was stirred 18h at rtand evaporated to dryness. The residue was purified by SiO₂chromatography (Hex/EtOAc 15 to 100% gradient) to afford the titlecompound (144 mg, 0.205 mmol, 97%) as a light yellow oil.

(1S,3R)—N-(4-aminophenyl)-3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexanecarboxamide.TFA

A solution of tert-butyl44(1S,3R)-3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexanecarboxamido)phenylcarbamate(144 mg, 0.21 mmol) in DCM (1 mL) was treated with TFA (0.16 mL, 2.05mmol) and stirred 1h at rt. The mixture was evaporated to dryness toafford the title compound (142 mg, 0.811 mmol, 97%) as a yellow solid.

(1S,3R)—N-(4-aminophenyl)-3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexanecarboxamide

A solution of(1S,3R)—N-(4-aminophenyl)-3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexanecarboxamide.TFA(142 mg, 0.20 mmol) in dioxane (1.4 mL) was treated with a 5M solutionof NaOH in H₂O (0.81 mL, 4.07 mmol) and stirred at 75° C. for 3h. Thecooled mixture was evaporated to dryness and H₂O (2 mL) was added to theresidue. The resulting solid was filtered, washed with H₂O (2×1 mL), anddried under high vacuum leaving the title compound (90 mg, 0.195 mmol,96%) as a white solid.

Example 5.4-amino-N-((1S,3R)-3-(5-cyclopropyl-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)benzamide.HCl(Compound 103) benzyl (1S,3R)-3-aminocyclohexylcarbamate.HCl

A solution of (1R,3S)-3-(Benzyloxycarbonylamino)cyclohexylamino2,2-dimethylpropionate prepared similarly to Example 3 (1.50 g, 4.31mmol) in DCM (43 mL) was treated with a 4M solution of HCl in dioxane(16 mL, 64.6 mmol) and stirred 2h at rt. The resulting solution wasevaporated to dryness to afford the title compound (1.23 g, 4.31 mmol,100%) as a white solid which was used in the next step without furtherpurification.

benzyl (1S,3R)-3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexylcarbamate

A solution of3-(2,5-dichloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole (791 mg,1.96 mmol), benzyl (1S,3R)-3-aminocyclohexylcarbamate (613 mg, 2.15mmol) and diisopropylethylamine (0.75 mL, 4.31 mmol) in NMP (20.0 mL)was heated 30 min at 135° C. (mW). The mixture was diluted with EtOAc(100 mL), washed with H₂O (50 mL), brine (50 mL), dried (MgSO₄),filtered and evaporated to dryness. The residue was purified by SiO₂chromatography (Hex/EtOAc 5 to 70% gradient), to afford the titlecompound (1.04 g, 1.69 mmol, 40%) as a yellow solid.

Benzyl(1S,3R)-3-(5-cyclopropyl-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexylcarbamate

A degassed solution of benzyl(1S,3R)-3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexylcarbamate(prepared similarly to Example 3) (500 mg, 0.812 mmol), Cs₂CO₃ (794 mg,2.435 mmol) and potassium cyclopropyltrifluoroborate (360 mg, 2.435mmol) in 2/1 toluene/H₂O (15 mL) was treated with a premixed solution ofPd(OAc)₂ (9 mg, 0.04 mmol) and butyldi-1-adamantylphosphine (29 mg, 0.08mmol) in degassed toluene (2 mL) and heated at 140° C. (microwave) for2h. The cooled mixture was diluted with EtOAc (50 mL) and saturatedNaHCO₃ (20 mL). The layers were separated and the aqueous layer wasextracted with EtOAc (2×20 mL). The combined organic layers were driedover Na₂SO₄, filtered and evaporated to dryness. The residue waspurified by SiO₂ chromatography (Hex/EtOAc 0 to 60% gradient) to affordthe title compound (324 mg, 0.521 mmol, 64%) as a pale yellow solid.

(1R,3S)—N¹-(5-cyclopropyl-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)cyclohexane-1,3-diamine

A degassed solution of benzyl(1S,3R)-3-(5-cyclopropyl-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexylcarbamate(778 mg, 1.250 mmol) in MeOH (60 mL) was treated with 10% wet Pd/C (150mg) and stirred under H₂ (1 atm) for 6h. The mixture was filtered oncelite (MeOH) and the filtrate was evaporated to dryness to afford thetitle compound (610 mg, 1.25 mmol, 75%) as a white foam which was usedin the next step without further purification.

tert-butyl 4-((1S,3R)-3-(5-cyclopropyl-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexylcarbamoyl)phenylcarbamate

A solution of(1R,3S)—N¹-(5-cyclopropyl-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)cyclohexane-1,3-diamine(457 mg, 0.937 mmol) and 4-(tert-butoxycarbonylamino)benzoic acid (245mg, 1.031 mmol) in DMF (10 mL) was treated with HBTU (533 mg, 1.406mmol) and DIPEA (245 μL, 1.406 mmol). The resulting mixture was stirredovernight at rt and diluted with EtOAc (50 mL) and saturated NaHCO₃ (20mL). The layers were separated and the aqueous layer was extracted withEtOAc (2×30 mL). The combined organic layers were dried over Na₂SO₄,filtered, and evaporated to dryness leaving the title compound (662 mg,0.936 mmol, 100%) as a yellow solid which was used in the next stepwithout further purification.

tert-butyl 4-((1S,3R)-3-(5-cyclopropyl-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexylcarbamoyl)phenylcarbamate

A solution of tert-butyl44(1S,3R)-3-(5-cyclopropyl-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexylcarbamoyl)phenylcarbamate(663 mg, 0.938 mmol) in dioxane (10 mL) was treated with a 2M solutionof NaOH (7 mL, 14 mmol) and heated at 70° C. for 1 h. The cooled mixturewas diluted with MeTHF (20 mL) and the layers were separated. Theaqueous layer was extracted with MeTHF (3×20 mL) and the combinedorganic layers were dried over Na₂SO₄, filtered, and evaporated todryness affording the title compound (531 mg, 0.937 mmol, 99.9%) as apale yellow solid which was used in the next step without furtherpurification.

4-amino-N-((1S,3R)-3-(5-cyclopropyl-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)benzamide.HCl

A solution of tert-butyl44(1S,3R)-3-(5-cyclopropyl-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexylcarbamoyl)phenylcarbamate(531 mg, 0.938 mmol) in DCM (10 mL) was treated with a 4M solution ofHCl in dioxane (3.50 mL, 14.0 mmol) and stirred 2h at rt. The resultingmixture was evaporated to dryness to afford the title compound (471 mg,0.938 mmol, 100%) as a white solid.

Example 6.4-amino-N-((1S,3R)-3-(5-chloro-4-(pyridin-3-yl)pyrimidin-2-ylamino)cyclohexyl)benzamide(Compound 108) tert-butyl (1 S,3R)-3-(5-chloro-4-(pyridin-3-yl)pyrimidin-2-ylamino)cyclohexylcarbamate

A solution of 2,5-dichloro-4-(pyridin-3-yl)pyrimidine (173 mg, 0.0.764mmol), tert-butyl (1S,3R)-3-aminocyclohexylcarbamate (182 mg, 0.849mmol), and DIPEA (0.16 mL, 0.892 mmol) in NMP (7.1 mL) was heated at135° C. (mW) for 60 min. The cooled mixture was diluted with EtOAc (30mL), washed with H₂O (10 mL), brine (10 mL), dried over MgSO₄, filtered,and evaporated to dryness. The residue was purified by SiO₂chromatography (DCM/EtOAc 0 to 70% gradient) to afford the titlecompound (185 mg, 0.458 mmol, 54%) as a light yellow foam.

(1R,3S)—N¹-(5-chloro-4-(pyridin-3-yl)pyrimidin-2-yl)cyclohexane-1,3-diamine.HCl

A solution of tert-butyl(1S,3R)-3-(5-chloro-4-(pyridin-3-yl)pyrimidin-2-ylamino)cyclohexylcarbamate(210 mg, 0.520 mmol) in DCM (2.6 mL) was treated with a 4M solution ofHCl in dioxane (1.3 mL, 5.130 mmol) and stirred 2h at rt. The resultingmixture was evaporated to dryness to afford the title compound (177 mg,0.520 mmol, 100%) as a light yellow solid which was used in the nextstep without further purification.

tert-butyl 4-((1S,3R)-3-(5-chloro-4-(pyridin-3-yl)pyrimidin-2-ylamino)cyclohexylcarbamoyl)phenylcarbamate

A solution of(1R,3S)—N¹-(5-chloro-4-(pyridin-3-yl)pyrimidin-2-yl)cyclohexane-1,3-diamine.HCl(297 mg, 0.783 mmol) and 4-(tert-butoxycarbonylamino)benzoic acid (149mg, 0.626 mmol) in DMF (5.2 mL) was treated with HBTU (297 mg, 0.783mmol) and DIPEA (364 μL, 2.087 mmol). The resulting mixture was stirredovernight at rt and diluted with EtOAc (30 mL) and saturated NaHCO₃ (15mL). The layers were separated and the aqueous layer was extracted withEtOAc (2×30 mL). The combined organic layers were dried over MgSO₄,filtered, and evaporated to dryness. The residue was purified by SiO₂chromatography (DCM/EtOAc, 0 to 100% gradient) to afford the titlecompound (227 mg, 0.434 mmol, 83%) as a light yellow solid.

4-amino-N-((1S,3R)-3-(5-chloro-4-(pyridin-3-yl)pyrimidin-2-ylamino)cyclohexyl)benzamide

A solution of tert-butyl4-((1S,3R)-3-(5-chloro-4-(pyridin-3-yl)pyrimidin-2-ylamino)cyclohexylcarbamoyl)phenylcarbamate(166 mg, 0.317 mmol) in DCM (3.2 mL) was treated with a 4M solution ofHCl in dioxane (0.79 mL, 3.17 mmol) and stirred 16h at rt. The resultingmixture was evaporated to dryness and diluted with EtOAc (20 mL) andsaturated NaHCO₃ (10 mL). The layers were separated and the aqueouslayer was extracted with EtOAc (3×15 mL). The combined organic layerswere dried over MgSO₄, filtered, and evaporated to dryness to afford thetitle compound (134 mg, 0.317 mmol, 100%) as a white solid.

Example 7.4-amino-N-((1S,3R)-3-(5-cyano-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)benzamide(Compound 107) 4-amino-N-((1S,3R)-3-(5-cyano-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)benzamide

A degassed solution of4-amino-N-((1S,3R)-3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)benzamide(prepared as in example 3) (222 mg, 0.369 mmol) in DMA (4 mL) wastreated with a premixed and degassed solution of Zn (2.4 mg, 0.04 mmol),Pd₂dba₃ (33.8 mg, 0.04 mmol), X-Phos (35.2 mg, 0.07 mmol) and Zn(CN)₂(26.0 mg, 0.22 mmol) in DMA (3 mL) and heated at 95° C. for 18h. Thecooled mixture was diluted with EtOAc (40 mL), washed with H₂O (10 mL),brine (10 mL), dried over MgSO₄, filtered, and evaporated to dryness.The residue was purified by SiO₂ chromatography (DCM/EtOAc 0 to 70%gradient) to afford the title compound (113 mg, 0.191 mmol, 52%) as alight yellow solid.

4-amino-N-((1S,3R)-3-(5-cyano-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)benzamide

A solution of4-amino-N4(1S,3R)-3-(5-cyano-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)benzamide(33 mg, 0.0549 mmol) in dioxane (3.8 mL) was treated with a 5M solutionof NaOH (50 μL, 0.275 mmol) and heated at 50° C. for 43h. The cooledmixture was treated with a 1M solution of HCl until a pH of 3 wasreached, and then the mixture was evaporated to dryness. The residue waspurified by reverse phase chromatography (C₁₈, H₂O/ACN+0.1% HCO₂H 80 to100% gradient) to afford the title compound (48 mg, 0.106 mmol, 55%) asa white solid after lyophilisation.

Example 8.(+/−)-4-amino-N-(3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)-5-fluorocyclohexyl)benzamide(Compound 110) (+/−)-1,3-diazido-5-fluorocyclohexane

A cooled (−78° C.) solution of (+/−)-3,5-diazidocyclohexanol (preparedfollowing New J. Chem., 2005, 29, 1152-1158) in DCM (30 mL) was treateddropwise with Me-DAST (268 μL, 2.74 mmol) and stirred 18h at thistemperature. A saturated solution of NaHCO₃ (10 mL) was added, thelayers were separated and the aqueous layer was extracted with EtOAc(3×10 mL). The combined organic layers were dried over MgSO₄, filteredand evaporated to dryness. The residue was purified by SiO₂chromatography (Hex/Et₂O 0 to 5% gradient) and afforded the titlecompound (141 mg, 0.349 mmol, 35%) as a colorless oil.

(+/−)-5-fluorocyclohexane-1,3-diamine

A degassed solution of (+/−)-1,3-diazido-5-fluorocyclohexane (141 mg,0.77 mmol) in MeOH (5 mL) was treated with 10% Pd/C (81 mg, 0.08 mmol)and stirred under H₂ (1 atm) for 5h. The resulting mixture was filteredover celite (MeOH) and the filtrate was evaporated to dryness affordingthe title compound (77 mg, 0.583 mmol, 76%) as a beige solid which wasused in the next step without further purification.

(+/−)-tert-butyl4-(-3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)-5-fluorocyclohexylcarbamoyl)phenylcarbamate

A solution of3-(2,5-dichloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole (180 mg,0.45 mmol), (+/−)-5-fluorocyclohexane-1,3-diamine (77 mg, 0.58 mmol) andDIPEA (101 μL, 3.54 mmol) in NMP (3 mL) was heated at 135° C. (mW) for25 min. The cooled mixture was then treated with4-(tert-butoxycarbonylamino)benzoic acid (93 mg, 0.45 mmol), HBTU (338mg, 0.89 mmol), and DIPEA (0.23 mL, 1.34 mmol). The resulting mixturewas stirred overnight at rt and then diluted with EtOAc (30 mL) andsaturated NaHCO₃ (10 mL). The layers were separated and the aqueouslayer was extracted with EtOAc (3×10 mL). The combined organic layerswere washed with brine (10 mL), dried over MgSO₄, filtered, andevaporated to dryness. The residue was purified by SiO₂ chromatography(Hex/EtOAc 0 to 100% gradient) to afford the title compound (198 mg,0.275 mmol, 62%) as a brownish solid.

(+/−)-4-amino-N-(3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)-5-fluorocyclohexyl)benzamide.TFA

A solution of (+/−)-tert-butyl4-(-3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)-5-fluorocyclohexylcarbamoyl)phenylcarbamate(198 mg, 0.28 mmol) in DCM (1.2 mL) was treated with TFA (210 μL, 2.75mmol) and stirred 2h at rt. The mixture was evaporated to dryness toafford the title compound (205 mg, 0.28 mmol, 100%) as a pale yellowsolid which was used in the next step without further purification.

(+/−)-4-amino-N-(3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)-5-fluorocyclohexyl)benzamide

A solution of(+/−)-4-amino-N-(3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)-5-fluorocyclohexyl)benzamide.TFA(256 mg, 0.36 mmol) in dioxane (2.4 mL) was treated with a 5M solutionof NaOH in H₂O (1.43 mL, 7.15 mmol) and heated at 75° C. overnight. Thecooled mixture was evaporated to dryness and the resulting solid wassuspended in H₂O (2 mL) and filtered. The solid was washed with H₂O (2×2ml) and dried under high vacuum to afford the title compound (96 mg,0.208 mmol, 58%) as a white solid which was used in the next stepwithout further purification.

4-amino-N-((1R,3S,5S)-3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)-5-fluorocyclohexyl)benzamide

Both enantiomers of(+/−)-4-amino-N-(3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)-5-fluorocyclohexyl)benzamide(76 mg, 0.165 mmol) were separated using preparative chiral HPLC(ChiralPak IB, 5 μm, 20×250 mm; Hex/MeOH/DCM 70/15/15) and afforded thetitle compound (21.9 mg, 0.047, 29%) as a white solid.

Example 9.4-amino-N-(5-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)bicyclo[3.1.1]heptan-1-yl)benzamide(Compound 104)N¹-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)bicyclo[3.1.1]heptane-1,5-diamine

A solution of3-(2,5-dichloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole (300 mg,0.742 mmol), bicyclo[3.1.1]heptane-1,5-diamine (prepared as inWO2006012395) (120 mg, 0.951 mmol) and DIPEA (142 μL, 0.816 mmol) in NMP(5 mL) was heated at 135° C. (mW) for 2h. The cooled mixture was dilutedwith EtOAc (30 mL), washed with H₂O (10 mL), brine (10 mL), dried overMgSO₄, filtered, and evaporated to dryness. The residue was purified bySiO₂ chromatography (DCM/MeOH 0 to 20% gradient) to afford the titlecompound (202 mg, 0.409 mmol, 55%) as a yellow foam.

tert-butyl4-(5-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)bicyclo[3.1.1]heptan-1-ylcarbamoyl)phenylcarbamate

A solution ofN¹-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)bicyclo[3.1.1]heptane-1,5-diamine(202 mg, 0.409 mmol) and 4-(tert-butoxycarbonylamino)benzoic acid (116mg, 0.491 mmol) in DMF (5.0 mL) was treated with HBTU (233 mg, 0.613mmol) and DIPEA (105 μL, 0.818 mmol). The resulting mixture was stirredovernight at rt and diluted with EtOAc (30 mL) and saturated NaHCO₃ (15mL). The layers were separated and the aqueous layer was extracted withEtOAc (2×30 mL). The combined organic layers were dried over MgSO₄,filtered, and evaporated to dryness to afford the title compound (291mg, 0.408 mmol, 100%) as a brown oil which was used in the next stepwithout further purification.

4-amino-N-(5-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)bicyclo[3.1.1]heptan-1-yl)benzamide.TFA

A solution of tert-butyl4-(5-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)bicyclo[3.1.1]heptan-1-ylcarbamoyl)phenylcarbamate(291 mg, 0.408 mmol) in DCM (4 mL) was treated with TFA (1.56 mL, 20.4mmol) and stirred 1h at rt. The mixture was evaporated to dryness toafford the title compound (250 mg, 0.408 mmol, 100%) as a yellowish oil.

4-amino-N-(5-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)bicyclo[3.1.1]heptan-1-yl)benzamide

A solution of4-amino-N-(5-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)bicyclo[3.1.1]heptan-1-yl)benzamide.TFA(250 mg, 0.408 mmol) in dioxane (10 mL) was treated with a 1M solutionof NaOH (6.0 mL, 6.0 mmol) and heated at 75° C. for 1 h. The cooledmixture was diluted with Me-THF (30 mL) and the organic layer was washedwith H₂O (10 mL), dried over MgSO₄, filtered, and evaporated to drynessto afford the title compound (193 mg, 0.408 mmol, 100%) as a creamysolid.

Example 10.4-amino-N-41R,5S)-5-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)-3,3-difluorocyclohexyl)benzamide(Compound 115)(+/−)-dibenzyl-5,5-difluorocyclohexane-1,3-diyldicarbamate

A solution of (+/−)-5,5-difluorocyclohexane-1,3-dicarboxylic acid(prepared as in WO2011005608) (454 mg, 2.18 mmol) in toluene (10 mL) wastreated with Et₃N (670 μL, 4.80 mmol) and DPPA (940 μL, 4.36 mmol) andheated at 110° C. for 1 h. The solution was cooled to 80° C. and treatedwith Et₃N (670 μL, 4.80 mmol) and BnOH (500 μL, 4.80 mmol) and stirredovernight at this temperature. The cooled mixture was diluted with EtOAc(50 mL) and H₂O (20 mL). The layers were separated and the aqueous layerwas extracted with EtOAc (3×20 mL). The combined organic layers weredried over MgSO₄, filtered, and evaporated to dryness. The residue wastriturated with Hex (10 mL) followed by Et₂O (5 mL) and the solid wasfiltered and washed with Hex to afford the title compound (694 mg, 1.66mmol, 76%) as a creamy solid which was used in the next step withoutfurther purification.

(+/−)-5,5-difluorocyclohexane-1,3-diamine

A degassed solution of(+/−)-dibenzyl-5,5-difluorocyclohexane-1,3-diyldicarbamate (694 mg, 1.66mmol) in MeOH (100 mL) was treated with 10% Pd/C (100 mg) and stirred 5hunder H₂ (1 atm). The resulting mixture was filtered over celite (MeOH)and the filtrate was evaporated to dryness to afford the title compound(249 mg, 1.66 mmol, 100%) as a colorless oil which was used in the nextstep without further purification.

(+/−)-N¹-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)-5,5-difluorocyclohexane-1,3-diamine

A solution of3-(2,5-dichloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole (560 mg,1.380 mmol), (+/−)-5,5-difluorocyclohexane-1,3-diamine (249 mg, 1.658mmol), and DIPEA (264 μL, 1.518 mmol) in NMP (15 mL) was heated at 135(mW) for 40 min. The cooled mixture was diluted with EtOAc (50 mL),washed with H₂O (10 mL), brine (10 mL), dried over MgSO₄, filtered, andevaporated to dryness. The residue was purified by SiO₂ chromatography(DCM/MeOH 0 to 20% gradient) to afford the title compound (192 mg, 0.371mmol, 27%) as a yellow foam.

(+/−)-tert-butyl4-(5-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)-3,3-difluorocyclohexylcarbamoyl)phenylcarbamate

A solution of(+/−)-N¹-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)-5,5-difluorocyclohexane-1,3-diamine(192 mg, 0.370 mmol) and 4-(tert-butoxycarbonylamino)benzoic acid (105mg, 0.444 mmol) in DMF (6.0 mL) was treated with HBTU (211 mg, 0.555mmol) and DIPEA (129 μL, 0.740 mmol). The resulting mixture was stirredovernight at rt and diluted with EtOAc (30 mL) and saturated NaHCO₃ (15mL). The layers were separated and the aqueous layer was extracted withEtOAc (2×30 mL). The combined organic layers were dried over MgSO₄,filtered and evaporated to dryness to afford the title compound (272 mg,0.370 mmol, 100%) as a brown oil which was used in the next step withoutfurther purification.

(+/−)-4-amino-N-(5-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)-3,3-difluorocyclohexyl)benzamide.TFA

A solution of (+/−)-tert-butyl4-(5-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)-3,3-difluorocyclohexylcarbamoyl)phenylcarbamate(272 mg, 0.370 mmol) in DCM (4 mL) was treated with TFA (1.45 mL, 19.0mmol) and stirred 2h at rt. The resulting mixture was evaporated todryness to afford the title compound (235 mg, 0.370 mmol, 100%) as abrownish oil which was used in the next step without furtherpurification.

(+/−)-4-amino-N-(5-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)-3,3-difluorocyclohexyl)benzamide

A solution of(+/−)-4-amino-N-(5-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)-3,3-difluorocyclohexyl)benzamide.TFA(235 mg, 0.370 mmol) in dioxane (10 mL) was treated with a 1M solutionof NaOH in H₂O (6.0 mL, 6.0 mmol) and heated at 75° C. for 2. Thevolatiles were removed by evaporation and the aqueous layer wasextracted with MeTHF (30 mL). The organic layer was washed with H₂O (10mL), dried over Na₂SO₄, filtered, and evaporated to dryness to affordthe title compound (157 mg, 0.316 mmol, 85%) as a yellow solid which wasused in the next step without further purification.

4-amino-N-((1R,5S)-5-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)-3,3-difluorocyclohexyl)benzamide

Both enantiomers of(+/−)-4-amino-N-(5-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)-3,3-difluorocyclohexyl)benzamide(62 mg, 0.125 mmol) were separated using preparative chiral HPLC(ChiralPak IB, 5 μm, 20×250 mm; Hex/MeOH/DCM 64/18/18) and afforded thetitle compound (19.1 mg, 0.038, 31%) as a white solid.

Example 11.4-amino-N-((1S,3R)-3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)benzenesulfonamide(Compound 109) N-((1S,3R)-3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)-4-nitrobenzenesulfonamide

A solution of(1R,3S)—N1-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)cyclohexane-1,3-diamineprepared as in example 3 (150 mg, 0.289 mmol) in pyr (2.2 mL) wastreated with 4-nitrobenzene-1-sulfonyl chloride (64 mg, 0.289 mmol) andheated at 90° C. for 16h. The cooled mixture was evaporated to drynessand the residue was purified by SiO₂ chromatography (DCM/EtOAc 0 to 100%gradient) to afford the title compound (147 mg, 0.220 mmol, 76%) as ayellow foam.

4-amino-N-((1S,3R)-3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)benzenesulfonamide

A solution ofN-((1S,3R)-3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)-4-nitrobenzenesulfonamide(147 mg, 0.223 mmol) in 5/1 EtOAc/MeOH (4 mL) was treated withSnCl₂.10H₂O (126 mg, 0.557 mmol) and heated at 90° C. in a sealed tubefor 4h. The cooled mixture was diluted with saturated NaHCO₃ (10 mL),and then the mixture was stirred 20 min at rt followed by extraction ofthe aqueous layer with 4/1 CHCl₃/IPA (3×30 mL). The combined organiclayers were washed with H₂O (10 mL), brine (10 mL), dried over MgSO₄,filtered through a pad of celite (4/1 CHCl₃/IPA), and evaporated todryness. The residue was purified by SiO₂ chromatography (DCM/EtOAc 0 to80% gradient) to afford the title compound (109 mg, 0.171 mmol, 77%) asa colorless oil.

4-amino-N-((1S,3R)-3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)benzenesulfonamide

A solution of4-amino-N-((1S,3R)-3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)benzenesulfonamide(109 mg, 0.171 mmol) in dioxane (3.4 mL) was treated with a 5M solutionof NaOH in H₂O (0.17 μL, 0.855 mmol) and heated at 50° C. overnight. Thecooled mixture was treated with a 1M solution of HCl in H₂O until a pHof 7 was reached, then the mixture was evaporated to dryness. Theresidue was purified by SiO₂ chromatography (DCM/MeOH 0 to 20% gradient)to afford the title compound (50 mg, 0.101 mmol, 59%) as a light yellowsolid.

Example 12.4-amino-N-((1S,3R)-3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)-2-fluorobenzamide(Compound 112)N-((1S,3R)-3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)-2-fluoro-4-nitrobenzamide

A solution of(1R,3S)—N1-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)cyclohexane-1,3-diamine.HClprepared as in example 3 (150 mg, 0.29 mmol) and 2-fluoro-4-nitrobenzoicacid (54 mg, 0.29 mmol) in DCM (1.9 mL) was treated with HBTU (219 mg,0.58 mmol) and DIPEA (150 μL, 0.870 mmol). The resulting mixture wasstirred overnight at rt and diluted with EtOAc (30 mL) and saturatedNaHCO₃ (15 mL). The layers were separated and the aqueous layer wasextracted with EtOAc (2×30 mL). The combined organic layers were driedover MgSO₄, filtered, and evaporated to dryness. The residue waspurified by SiO₂ chromatography (DCM/EtOAc 0 to 50% gradient) to affordthe title compound (174 mg, 0.268 mmol, 93%) as a beige solid.

4-amino-N-((1S,3R)-3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)-2-fluorobenzamide

A solution ofN-((1S,3R)-3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)-2-fluoro-4-nitrobenzamide(174 mg, 0.27 mmol) in 5/1 EtOAc/MeOH (5 mL) was treated withSnCl₂.10H₂O (151 mg, 0.67 mmol) and heated at 80° C. in a sealed tubefor 5h. The cooled mixture was diluted with saturated NaHCO₃ (10 mL),and the mixture was stirred 20 min at rt followed by extraction of theaqueous layer with EtOAc (3×30 mL). The combined organic layers werewashed with H₂O (10 mL), brine (10 mL), dried over MgSO₄, filtered, andevaporated to dryness to afford the title compound (147 mg, 0.237 mmol,88%) as a pale yellow solid which was used in the next step withoutfurther modification.

4-amino-N-((1S,3R)-3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)-2-fluorobenzamide

A solution of4-amino-N-((1S,3R)-3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)-2-fluorobenzamide(146 mg, 0.24 mmol) in dioxane (1.6 mL) was treated with a 5M solutionof NaOH in H₂O (940 μL, 4.72 mmol) and heated at 75° C. overnight. Thecooled mixture was diluted with MeTHF (20 mL) and H₂O (10 mL). Thelayers were separated and the aqueous layer was extracted with MeTHF(3×15 mL). The combined organic layers were dried over MgSO₄, filtered,and evaporated to dryness. The residue was purified by SiO₂chromatography (DCM/THF 0 to 60% gradient) to afford the title compound(98 mg, 0.205 mmol, 67%) as a white solid.

Example 13.4-amino-N-((1S,3R)-3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)-3-fluorobenzamide(Compound 111)4-amino-N-((1S,3R)-3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)-3-fluorobenzamide

A solution of(1R,3S)—N1-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)cyclohexane-1,3-diamine.HClprepared as in example 3 (150 mg, 0.29 mmol) and 4-amino-3-fluorobenzoicacid (45 mg, 0.29 mmol) in DMF (1.9 mL) was treated with HBTU (219 mg,0.58 mmol) and DIPEA (150 μL, 0.870 mmol). The resulting mixture wasstirred overnight at rt and diluted with MeTHF (30 mL) and saturatedNaHCO₃ (15 mL). The layers were separated and the aqueous layer wasextracted with MeTHF (2×30 mL). The combined organic layers were driedover MgSO₄, filtered, and evaporated to dryness. The residue waspurified by SiO₂ chromatography (DCM/EtOAc 0 to 100% gradient) to affordthe title compound (178 mg, 0.287 mmol, 99%) as a pale yellow solid.

4-amino-N-((1S,3R)-3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)-3-fluorobenzamide

A solution of4-amino-N4(1S,3R)-3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)-3-fluorobenzamide(179 mg, 0.29 mmol) in dioxane (1.9 mL) was treated with a 5M solutionof NaOH in H₂O (1.16 mL, 5.78 mmol) and heated at 75° C. overnight. Thecooled mixture was diluted with MeTHF (20 mL) and H₂O (10 mL). Thelayers were separated and the aqueous layer was extracted with MeTHF(3×15 mL). The combined organic layers were dried over MgSO₄, filtered,and evaporated to dryness. The residue was purified by SiO₂chromatography (DCM/THF 0 to 60% gradient) to afford the title compound(89 mg, 0.185 mmol, 64%) as a white solid.

Example 14.(+/−)-4-amino-N-(3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)-1-methylcyclohexyl)benzamide(Compound 116) tert-butyl (1R, 3S)-3-(Benzyloxycarbonylamino)-3-methylcyclohexylcarbamate

A solution of(1S,3R)-3-(tert-butoxycarbonylamino)-1-methylcyclohexane-carboxylic acid(prepared as in WO2010/148197, 100 mg, 0.389 mmol) in toluene (1.5 mL)was treated with Et₃N (60 μL, 0.43 mmol) and DPPA (84 μL, 0.39 mmol) andheated at 110° C. for 1 h. The mixture was cooled down to 80° C.,treated with benzyl alcohol (42 μL, 0.41 mmol) and Et₃N (60 μL, 0.43mmol). The resulting mixture was heated at 80° C. for 20h. The cooledmixture was then diluted with EtOAc (20 mL) and H₂O (10 mL). The layerswere separated and the aqueous layer was extracted with EtOAc (3×10 mL).The combined organics layers were washed with brine (10 mL), filtered,and evaporated to dryness. The residue was purified by SiO₂chromatography (Hex/EtOAc 0 to 50% gradient) to afford the titlecompound (59 mg, 0.180 mmol, 46%) as a colorless oil.

(+/−)-benzyl-3-amino-1-methylcyclohexylcarbamate.HCl

A solution of tert-butyl(1R,3S)-3-(benzyloxycarbonylamino)-3-methylcyclohexylcarbamate (45 mg,0.124 mmol) in DCM (0.6 mL) was treated with a 4M solution of HCl indioxane (620 μL, 2.48 mmol) and stirred 1h at rt. The mixture wasevaporated to dryness to afford the title compound (37 mg, 0.124 mmol,100%) as a white solid which was used in the next step without furtherpurification.

(+/−)-benzyl-3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)-1-methylcyclohexylcarbamate

A solution of3-(2,5-dichloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole (63 mg,0.155 mmol), (+/−)-benzyl-3-amino-1-methylcyclohexylcarbamate.HCl (37mg, 0.124 mmol) and DIPEA (44 μL, 0.254 mmol) in NMP (0.5 mL) was heatedat 135° C. (mW) for 25 min. The cooled mixture was diluted with EtOAc(20 mL), washed with H₂O (5 mL), brine (5 mL), dried over MgSO₄,filtered, and evaporated to dryness. The residue was purified by SiO₂chromatography (DCM/EtOAc 0 to 30% gradient) to afford the titlecompound (52 mg, 0.083 mmol, 66%) as a yellow foam.

(+/−)-N1-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)-3-methylcyclohexane-1,3-diamine

A cooled (−78° C.) solution of(+/−)-benzyl-3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)-1-methylcyclohexylcarbamate(51 mg, 0.081 mmol) in DCM (0.32 mL) was treated with a 1M solution ofBBr₃ in DCM (97 μL, 0.097 mmol) and was slowly warmed to rt. MeOH (1 ML)was added to the mixture was the resulting solution was stirred 1h atrt. The resulting mixture was evaporated to dryness to afford the titlecompound (40 mg, 0.081 mmol, 100%) as a yellow solid which was used inthe next step without further purification.

(+/−)-tert-butyl4-(3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)-1-methylcyclohexylcarbamoyl)phenylcarbamate

A solution of(+/−)-benzyl-3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)-1-methylcyclohexylcarbamate(40 mg, 0.81 mmol) and 4-(tert-butoxycarbonylamino)benzoic acid (23 mg,0.97 mmol) in DMF (0.4 mL) was treated with HBTU (46 mg, 0.121 mmol) andEt₃N (34 μL, 0.242 mmol). The resulting mixture was stirred overnight atrt and diluted with EtOAc (10 mL) and saturated NaHCO₃ (10 mL). Thelayers were separated and the aqueous layer was extracted with EtOAc(2×10 mL). The combined organic layers were dried over MgSO₄, filtered,and evaporated to dryness. The residue was purified by SiO₂chromatography (DCM/EtOAc 0 to 100% gradient) to afford the titlecompound (48 mg, 0.067 mmol, 83%) as a beige solid.

(+/−)-tert-butyl4-(3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)-1-methylcyclohexylcarbamoyl)phenylcarbamate

A solution of (+/−)-tert-butyl4-(3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)-1-methylcyclohexylcarbamoyl)phenylcarbamate(45 mg, 0.063 mmol) in dioxane (0.6 mL) was treated with a 2M solutionof NaOH in H₂O (472 μL, 0.944 mmol) and heated at 60° C. for 1 h. Thecooled mixture was diluted with MeTHF (20 mL) and H₂O (10 mL). Thelayers were separated and the aqueous layer was extracted with MeTHF(3×10 mL). The combined organic layers were dried over MgSO₄, filtered,and evaporated to dryness to afford the title compound (36 mg, 0.063mmol, 100%) as a yellow solid which was used in the next step withoutfurther purification.

(+/−)-4-amino-N-(3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)-1-methylcyclohexyl)benzamide

A solution of (+/−)-tert-butyl4-(3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)-1-methylcyclohexylcarbamoyl)phenylcarbamate(36 mg, 0.063 mmol) in DCM was treated with a 4M solution of HCl indioxane (235 μL, 0.939 mmol) and stirred overnight at rt. The resultingmixture was diluted with MeTHF (10 mL) and saturated NaHCO₃ (5 mL). Thelayers were separated and the aqueous layer was extracted with MeTHF(3×10 mL). The combine organic layers were dried over MgSO₄, filtered,and evaporated to dryness to afford the title compound (30 mg, 0.063mmol, 100%) as a pale yellow solid.

Example 15.N-((1S,3R)-3-(4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)-4-aminobenzamide(Compound 114) tert-butyl 4-((1S,3R)-3-(4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexylcarbamoyl)phenylcarbamate

A degassed solution of tert-butyl4-((1S,3R)-3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexylcarbamoyl)phenylcarbamateprepared as in example 3 (148 mg, 0.211 mmol) in MeOH (10 mL) wastreated with 10% Pd/C (25 mg) and stirred overnight under H₂ (50 psi).The resulting mixture was filtered over celite (MeOH) and the filtratewas evaporated to dryness affording an inseparable mixture of the titlecompound and chlorinated pyrimidine which was used in the next stepwithout purification.

N-((1S,3R)-3-(4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)-4-aminobenzamide

A solution of tert-butyl4-((1S,3R)-3-(4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexylcarbamoyl)phenylcarbamate(100 mg, as a mixture with chlorinated pyrimidine from previous step) inDCM (2.0 mL) was treated with a 4M solution of HCl in dioxane (750 mL,3.0 mmol) and stirred 4h at rt. The mixture was evaporated to drynessand the residue was purified by reverse phase chromatography (C₁₈,H₂O/ACN+0.1% HCO₂H 5 to 60% gradient) to afford the title compound (12.5mg, 0.0081 mmol, 25%) as a white solid.

Example 16.4-amino-N-((1S,3R)-3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)-2-morpholinobenzamide(Compound 117) 2-morpholino-4-nitrobenzoic acid

A solution of methyl 2-fluoro-4-nitrobenzoate (200 mg, 1.00 mmol) andmorpholine (703 μL, 8.04 mmol) in NMP (2.1 mL) was heated at 140° C.(mW) for 35 min. The cooled mixture was diluted with EtOAc (20 mL) andwashed with H₂O (10 mL) and brine (10 ml). The combined aqueous layerswere acidified to pH=2 with a 1M solution of HCl in H₂O and extractedwith DCM (3×20 mL). The combined organic layers were dried by passingthrough a phase cartridge separator and evaporated to dryness to affordthe title compound as a mixture with morpholine which was used in thenext step without further purification.

N-((1S,3R)-3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)-2-morpholino-4-nitrobenzamide

A solution of(1R,3S)—N1-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)cyclohexane-1,3-diamineprepared as in example 3 (50 mg, 0.104 mmol) and2-morpholino-4-nitrobenzoic acid (29 mg, 0.114 mmol) in DMF (5.0 mL) wastreated with Et₃N (43 μL, 0.311 mmol) and HBTU (59 mg, 0.156 mmol). Theresulting mixture was stirred overnight at rt, diluted with EtOAc (20mL) and saturated NaHCO₃ (10 mL). The layers were separated and theorganic layer was washed with brine (10 mL), dried over MgSO₄, filtered,and evaporated to dryness. The residue was purified by SiO₂chromatography (DCM/EtOAc 0 to 70% gradient) to afford the titlecompound (48 mg, 0.067 mmol, 65%) as a pale yellow solid.

4-amino-N-((1S,3R)-3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)-2-morpholinobenzamide

A cooled (0° C.) solution ofN-((1S,3R)-3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)-2-morpholino-4-nitrobenzamide(76 mg, 0.106 mmol) in 2/1 MeOH/THF (1 mL) was sequentially treated withNiCl₂.6H₂O (12.6 mg, 0.053 mmol) and NaBH₄ (16.1 mg, 0.425 mmol). Theblack resulting mixture was stirred 15 min at rt before dilution withEtOAc (20 mL) and H₂O (10 mL). The layers were separated and the aqueouslayer was extracted with EtOAc (3×10 mL). The combined organic layerswere washed with brine (10 mL), dried over MgSO₄, filtered, andevaporated to dryness. The residue was purified by SiO₂ chromatography(DCM/EtOAc 0 to 70% gradient) to afford the title compound (26 mg, 0.038mmol, 36%) as a pale yellow solid.

4-amino-N-((1S,3R)-3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)-2-morpholinobenzamide

A solution of4-amino-N-((1S,3R)-3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)-2-morpholinobenzamide(24 mg, 0.035 mmol) in dioxane (0.35 mL) was treated with a 2M solutionof NaOH in H₂O (262 μL, 0.525 mmol) and stirred overnight at rt and 2hat 60° C. The cooled mixture was concentrated to remove volatiles andthe resulting residue was diluted with MeTHF (15 mL) and H₂O (10 mL).The layers were separated and the aqueous layer was extracted with MeTHF(3×10 mL). The combined organic layers were dried over Na₂SO₄, filtered,and evaporated to dryness to afford the title compound (19 mg, 0.0248mmol, 71%) as a pale yellow solid.

Example 17.4-amino-N-((1B,3R)-3-(5-chloro-4-(1H-indol-3-yl)pyridin-2-ylamino)cyclohexyl)benzamide(Compound 118)3-(2-bromo-5-chloropyridin-4-yl)-1-(phenylsulfonyl)-1H-indole

A degassed solution of 2-bromo-5-chloro-4-iodopyridine (500 mg, 1.57mmol), 1-(phenylsulfonyl)-1H-indol-3-ylboronic acid (497 mg g, 1.65mmol), Cs₂CO₃ (1.023 g, 3.14 mmol) and Pd(PPh₃)₄ (181 mg, 0.16 mmol) in2/1 dioxane/H₂O (52 ml) was heated at 100° C. for 3h. The cooled mixturewas diluted with EtOAc (50 mL) and saturated NaHCO₃ (20 ml). The layerswere separated and the aqueous layer was extracted with EtOAc (3×20 mL).The combined organic layers were washed with brine (20 mL), dried overMgSO₄ and evaporated to dryness. The residue was purified by SiO₂chromatography (Hex/EtOAc 5 to 70% gradient) and afforded the titlecompound (373 mg, 0.836 mmol, 53%) as a pale yellow solid.

Benzyl(1S,3R)-3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyridin-2-ylamino)cyclohexylcarbamate

A solution of3-(2-bromo-5-chloropyridin-4-yl)-1-(phenylsulfonyl)-1H-indole (151 mg,0.34 mmol) and benzyl (1S,3R)-3-aminocyclohexylcarbamate prepared as inexample 8 (167 mg, 0.67 mmol) in DMSO (2.0 mL) was heated at 140° C. for24h. The cooled mixture was diluted with DCM (50 ml) and H₂O (50 ml).The layers were separated and the aqueous layer was extracted with DCM(3×20 mL). The combined organic layers were washed with H₂O (20 mL),brine (20 mL), dried over MgSO₄, filtered, and evaporated to dryness.The residue was purified by SiO₂ chromatography (DCM/MeOH 0 to 10%gradient) to afford the title compound (43 mg, 0.070 mmol, 21%) as awhite solid.

(1R,3S)—N1-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyridin-2-yl)cyclohexane-1,3-diamine

A cooled (−78° C.) solution of benzyl(1S,3R)-3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyridin-2-ylamino)cyclohexylcarbamate(42 mg, 0.068 mmol) in DCM (1.0 mL) was treated with a 1M solution ofBBr₃ in DCM (82 μL, 0.082 mmol) and stirred for 1h, then warmed up tort, and stirred for an additional 3h. The resulting mixture was treatedwith MeOH (2 mL) and the solution was evaporated to dryness. The residuewas purified by reverse phase chromatography (C₁₈, H₂O/ACN+0.1% HCO₂H 0to 100% gradient) to afford the title compound (10 mg, 0.021 mmol, 31%)as a pale yellow solid.

tert-butyl4-((1S,3R)-3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyridin-2-ylamino)cyclohexylcarbamoyl)phenylcarbamate

A solution of(1R,3S)—N1-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyridin-2-yl)cyclohexane-1,3-diamine(10 mg, 0.021 mmol) and 4-(tert-butoxycarbonylamino)benzoic acid (5.9mg, 0.025 mmol) in DMF (2.0 mL) was treated with DIPEA (5.4 μL, 0.031mmol) and HBTU (5.4 mg, 0.031 mmol). The resulting mixture was stirredovernight at rt, diluted with EtOAc (5 mL) and saturated NaHCO₃ (5 mL).The layers were separated and the organic layer was washed with brine (5mL), dried over MgSO₄, filtered, and evaporated to dryness to afford thetitle compound (14.6 mg, 0.021 mmol, 100%) as a pale yellow solid whichwas used in the next step without further purification.

4-amino-N-((1S,3R)-3-(5-chloro-4-(1H-indol-3-yl)pyridin-2-ylamino)cyclohexyl)benzamide

A solution of tert-butyl44(1S,3R)-3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyridin-2-ylamino)cyclohexylcarbamoyl)phenylcarbamate(14.6 mg, 0.021 mmol) in DCM (2 mL) was treated with TFA (82 μL, 1.07mmol) and stirred 3h at rt. The resulting solution was evaporated todryness, dissolved in dioxane (1 mL), treated with a 1M solution of NaOHin H₂O (315 μL, 0.315 mmol), and heated at 70° C. for 3h. The cooledmixture was evaporated to dryness and the residue was diluted with MeTHF(10 mL) and H₂O (5 mL). The layers were separated and the aqueous layerwas extracted with MeTHF (4×5 mL). The combined organic layers weredried over Na₂SO₄, filtered, and evaporated to dryness, affording thetitle compound (9.6 mg, 0.20 mmol, 94%) as a white gum.

Example 18.3-amino-N-(trans-4-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)benzamide.HCl(Compound 119)

(trans)-N1-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine

A solution of3-(2,5-dichloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole (500 mg,1.24 mmol), trans-1,4-diaminocyclohexane (170 mg, 1.49 mmol), and DIPEA(260 μL, 1.49 mmol) in NMP (15 mL) was heated at 135° C. (mW) for 40min. The cooled mixture was diluted with EtOAc (30 mL), washed with H₂O(60 mL), brine (60 mL), dried over Na₂SO₄, filtered, and evaporated todryness. The residue was purified by SiO₂ chromatography (DCM/MeOH 5 to30% gradient) to afford the title compound (298 mg, 0.618 mmol, 50%) asa white solid.

tert-butyl3-(trans-4-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexylcarbamoyl)phenylcarbamate

A solution of(trans)-N1-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)cyclohexane-1,4-diamine(125 mg, 0.260 mmol) and 3-(tert-butoxycarbonylamino)benzoic acid (69mg, 0.290 mmol) in DMF (2.5 mL) was treated with DIPEA (68 μL, 0.390mmol) and HBTU (148 mg, 0.390 mmol). The resulting mixture was stirredovernight at rt then diluted with EtOAc (20 mL) and saturated NaHCO₃ (10mL). The layers were separated and the aqueous layer was extracted withEtOAc (2×20 mL). The combined organic layers were washed with brine (10mL), dried over Na₂SO₄, filtered, and evaporated to dryness to affordthe title compound (182 mg, 0.290 mmol, 100%) as a yellow solid whichwas used in the next step without further purification.

tert-butyl3-(trans-4-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexylcarbamoyl)phenylcarbamate

A solution of tert-butyl3-(trans-4-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexylcarbamoyl)phenylcarbamate(182 mg, 0.290 mmol) in dioxane (3.0 mL) was treated with a 2M solutionof NaOH in H₂O (2.5 mL, 5.00 mmol) and stirred at 70° C. for 1 h. Thecooled mixture was evaporated to dryness and the residue was dissolvedin MeTHF (20 mL) and H₂O (10 mL). The layers were separated and theaqueous layer was extracted with MeTHF (3×10 mL). The combined organiclayers were dried over Na₂SO₄, filtered, and evaporated to dryness toafford the title compound (163 mg, 0.290 mmol, 100%) as a yellow solidwhich was used in the next step without further purification.

3-amino-N-(trans-4-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)benzamide.HCl

A solution of tert-butyl3-(trans-4-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexylcarbamoyl)phenylcarbamate(163 mg, 0.290 mmol) in DCM (3.0 mL) was treated with a 4M solution ofHCl in dioxane (1.10 mL, 4.54 mmol) and stirred 30 min at rt. Theresulting mixture was evaporated to dryness to afford the title compound(144 mg, 0.290 mmol, 100%) as a yellow solid.

Example 19.(1S,3R)—N1-((R)-1-(4-aminophenyl)-2,2,2-trifluoroethyl)-N3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)cyclohexane-1,3-diamine(Compound 120) tert-butyl (1R,3S)-3-(hydroxymethyl)cyclohexylcarbamate

A cooled (0° C.) solution of(1S,3R)-3-(tert-butoxycarbonylamino)-cyclohexanecarboxylic acid(prepared following Tetrahedron: Asymmetry 2010 (21), 864-866) (1.24 g,5.09 mmol) in THF (34 mL) was treated with a 2M solution of BH₃.Me₂S inTHF (3.7 mL, 7.38 mmol) and stirred overnight at rt. The resultingsolution was treated with a 1M solution of HCl in H₂O (20 mL) andextracted with EtOAc (3×20 mL). The combined organic layers were driedover MgSO₄, filtered, and evaporated to dryness affording the titlecompound (1.17 g, 5.09 mmol, 100%) as a colorless oil which was used inthe next step without further purification.

(R)-tert-butyl 3-methylenecyclohexylcarbamate

A cooled (0° C.) solution of tert-butyl(1R,3S)-3-(hydroxymethyl)cyclohexylcarbamate (200 mg, 0.87 mmol) intoluene (6 mL) was sequentially treated with imidazole (148 mg, 2.18mmol), PPh₃ (572 mg, 2.18 mmol) and I₂ (288 mg, 1.13 mmol). Theresulting mixture was stirred overnight at rt before being diluted witha saturated solution of NaHCO₃ (10 mL), a 5% solution of Na₂S₂O₃ (10mL), and DCM (30 mL). The layers were separated and the aqueous layerwas extracted with DCM (2×30 mL). The combined organic layers were driedover MgSO₄, filtered, and evaporated to dryness. The residue was takenback up in toluene (10 mL), treated with DBU (261 μL, 1.74 mmol), andheated overnight at 80° C. The cooled mixture was diluted with asaturated solution of NH₄Cl (10 mL) and EtOAc (20 mL). The layers wereseparated and the aqueous layer was extracted with EtOAc (3×20 mL). Thecombined organic layers were dried over MgSO₄, filtered, and evaporatedto dryness. The residue was purified by SiO₂ chromatography (Hex/EtOAc 5to 30% gradient) to afford the title compound (72 mg, 0.341 mmol, 39%)as a white solid.

(R)-tert-butyl 3-oxocyclohexylcarbamate

O₃ was bubbled into a cooled (−78° C.) solution of (R)-tert-butyl3-methylenecyclohexylcarbamate (424 mg, 2.01 mmol) in DCM (40 mL) for 30min, at which point PPh₃ (917 mg, 6.02 mmol) was added. The resultingmixture was warmed up to rt and evaporated to dryness. The residue waspurified by SiO₂ chromatography (Hex/EtOAc 0 to 60% gradient) andafforded the title compound (415 mg, 1.95 mmol, 97%) as a white solid.

tert-butyl(1R,3S)-3-((R)-1-(4-bromophenyl)-2,2,2-trifluoroethylamino)cyclohexylcarbamate

A solution of (R)-1-(4-bromophenyl)-2,2,2-trifluoroethanamine.HCl(prepared following Org. Lett. 2005, 7, 2, 355-358) (501 mg, 1.72 mmol)in DCE (16.4 mL) was sequentially treated with DIPEA (314 μL, 1.81mmol), AcOH (47 μL, 0.82 mmol), (R)-tert-butyl 3-oxocyclohexylcarbamate(350 mg, 1.64 mmol), and NaBH(OAc)₃ (522 mg, 2.46 mmol). The resultingmixture was stirred 16 at rt and then diluted with DCM (20 mL) and asaturated solution of NaHCO₃ (10 mL). The layers were separated and theorganic layer was washed with brine (10 mL), dried over MgSO₄, filtered,and evaporated to dryness. The residue was purified by SiO₂chromatography (Hex/EtOAc 5 to 50% gradient) to afford the titlecompound (356 mg, 0.789 mmol, 48%) as a white solid.(1S,3R)—N1-((R)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)cyclohexane-1,3-diamine.HCl

A solution of tert-butyl(1R,3S)-3-((R)-1-(4-bromophenyl)-2,2,2-trifluoroethylamino)cyclohexylcarbamate(144 mg, 0.32 mmol) in DCM (0.65 mL) was treated with a 4M solution ofHCl in dioxane (1.60 mL, 6.38 mmol) and stirred 1h at rt. The resultingmixture was evaporated to dryness to afford the title compound (121 mg,0.312 mmol, 98%) as a beige solid which was used in the next stepwithout further purification.

(1S,3R)—N1-((R)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)cyclohexane-1,3-diamine

A solution of3-(2,5-dichloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole (155 mg,0.380 mmol),(1S,3R)—N1-((R)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)cyclohexane-1,3-diamine.HCl(126 mg, 0.325 mmol) and DIPEA (200 μL, 1.15 mmol) in NMP (2.6 mL) washeated at 145° C. (mW) for 90 min. The cooled mixture was diluted withMeTHF (20 mL), washed with H₂O (10 mL), brine (10 mL), dried over MgSO₄,filtered, and evaporated to dryness. The residue was purified by SiO₂chromatography (Hex/EtOAc 0 to 100% gradient) to afford the titlecompound (141 mg, 0.196 mmol, 60%) as a pale yellow foam.

tert-butyl 4-((R)-1-((1S,3R)-3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexylamino)-2,2,2-trifluoroethyl)phenylcarbamate

A degassed solution of(1S,3R)—N1-((R)-1-(4-bromophenyl)-2,2,2-trifluoroethyl)-N3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)cyclohexane-1,3-diamine(141 mg, 0.196 mmol), t-butylcarbamate (28 mg, 0.24 mmol), Pd(OAc)₂ (1.3mg, 0.01 mmol), Xphos (8.4 mg, 0.02 mmol) and Cs₂CO₃ (90 mg, 0.27 mmol)in dioxane (2.0 mL) was heated at 90° C. for 12h. The cooled mixture wasfiltered over celite (EtOAc) and the filtrate was evaporated to dryness.The residue was purified by SiO₂ chromatography (Hex/EtOAc 0 to 100%gradient) to afford the title compound (191 mg as a mixture with unknownimpurity) as a pale yellow foam.

(1S,3R)—N1-((R)-1-(4-aminophenyl)-2,2,2-trifluoroethyl)-N3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)cyclohexane-1,3-diamine

A solution of tert-butyl4-((R)-14(1S,3R)-3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexylamino)-2,2,2-trifluoroethyl)phenylcarbamate(191 mg as a mixture with unknown impurity) in DCM (0.4 mL) was treatedwith a 4M solution of HCl in dioxane (730 μL, 2.94 mmol) and stirred 30min at rt. The resulting mixture was evaporated to dryness, suspended indioxane (1.3 mL) and treated with a 5M solution of NaOH in H₂O (590 μl,2.94 mmol). The resulting mixture was stirred 5h at rt and diluted withMeTHF (20 mL) and H₂O (10 mL). The layers were separated and the aqueouslayer was extracted with MeTHF (2×10 mL). The combined organic layerswere dried over MgSO₄, filtered, and evaporated to dryness. The residuewas purified by SiO₂ chromatography (DCM/THF 0 to 50% gradient) toafford the title compound (59 mg, 0.115 mmol, 58% over 2 steps) as apale yellow solid.

Example 20.4-amino-N-((1S,3R)-3-(5-fluoro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)benzamide.HCl(Compound 121)3-(2-chloro-5-fluoropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole

A degassed solution of 2,4-dichloro-5-fluoropyrimidine (500 mg, 2.99mmol), 1-(phenylsulfonyl)-1H-indol-3-ylboronic acid (947 mg g, 3.14mmol), Cs₂CO₃ (1.95 g, 5.99 mmol), and Pd(PPh₃)₄ (346 mg, 0.30 mmol) in2/1 dioxane/H₂O (30 ml) was heated overnight at 100° C. The cooledmixture was diluted with EtOAc (50 mL) and saturated NaHCO₃ (20 ml). Thelayers were separated and the aqueous layer was extracted with EtOAc(3×20 mL). The combined organic layers were washed with brine (20 mL),dried over MgSO₄ and evaporated to dryness. The residue was purified bySiO₂ chromatography (DCM) to afford the title compound (599 mg, 1.55mmol, 52%) as a pale orange oil.

tert-butyl-(1S,3R)-3-(5-fluoro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexylcarbamate

A solution of3-(2-chloro-5-fluoropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole (250mg, 0.64 mmol), tert-butyl (1S,3R)-3-aminocyclohexylcarbamate preparedas in example 3 (138 mg, 0.64 mmol) and DIPEA (237 μL, 1.93 mmol) in NMP(4.3 mL) was heated at 140° C. (microwave) for 60 min. The cooledmixture was diluted with MeTHF (30 mL), washed with H₂O (10 mL), brine(10 mL), dried over MgSO₄, filtered, and evaporated to dryness. Theresidue was purified by SiO₂ chromatography (DCM/EtOAc 0 to 30%gradient) to afford the title compound (76 mg, 0.134 mmol, 21%) as apale yellow solid.

(1R,3S)—N1-(5-fluoro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)cyclohexane-1,3-diamine.HCl

A solution of tert-butyl(1S,3R)-3-(5-fluoro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexylcarbamate(76 mg, 0.134 mmol) in dioxane (0.3 mL) was treated with a 4M solutionof HCl in dioxane (340 μL, 1.34 mmol) and stirred 1h at rt. Theresulting mixture was evaporated to dryness to afford the title compound(64 mg, 0.127 mmol, 95%) as a white solid which was used in the nextstep without further purification.

tert-butyl 4-((1S,3R)-3-(5-fluoro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexylcarbamoyl)phenylcarbamate

A solution of(1R,3S)—N1-(5-fluoro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)cyclohexane-1,3-diamine.HCl(64 mg, 0.127 mmol) and 4-(tert-butoxycarbonylamino)benzoic acid (27 mg,0.130 mmol) in DMF (0.85 mL) was treated with DIPEA (66 μL, 0.51 mmol)and HBTU (97 mg, 0.256 mmol). The resulting mixture was stirredovernight at rt, diluted with EtOAc (20 mL) and saturated NaHCO₃ (10mL). The layers were separated and the aqueous layer was extracted withEtOAc (2×20 mL). The combined organic layers were washed with brine (10mL), dried over Na₂SO₄, filtered and evaporated to dryness. The residuewas purified by SiO₂ chromatography (DCM/EtOAc 0 to 100% gradient) toafford the title compound (87 mg, 0.127 mmol, 100%) as a pale yellowsolid.

tert-butyl 44(1S,3R)-3-(5-fluoro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexylcarbamoyl)phenylcarbamate

A solution of tert-butyl44(1S,3R)-3-(5-fluoro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexylcarbamoyl)phenylcarbamate(87 mg, 0.127 mmol) in dioxane (0.85 ml) was treated with a 5M solutionof NaOH in H₂O (380 μL, 1.91 mmol) and heated at 65° C. for 5h. Thecooled mixture was evaporated to dryness and the residue was purified bySiO₂ chromatography (DCM/THF 0 to 50% gradient) to afford the titlecompound (59 mg, 0.108 mmol, 85%) as a pale yellow solid.

4-amino-N-((1S,3R)-3-(5-fluoro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)benzamide.HCl

A solution of tert-butyl4-((1S,3R)-3-(5-fluoro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexylcarbamoyl)phenylcarbamate(59 mg, 0.108 mmol) in dioxane (720 μL) was treated with a 4M solutionof HCl in dioxane (410 μL, 1.62 mmol) and stirred overnight at rt. Theresulting mixture was evaporated to dryness to afford the title compound(52 mg, 0.108 mmol, 100%) as a white solid.

Example 21.(1S,3R)—N1-(4-aminobenzyl)-N3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)-N1-methylcyclohexane-1,3-diamine.HCl(Compound 122) tert-butyl 4-(((1 S,3R)-3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexylamino)methyl)phenylcarbamate

A solution of(1R,3S)—N1-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)cyclohexane-1,3-diamineprepared as in example 3 (180 mg, 0.373 mmol), tert-butyl4-formylphenylcarbamate (124 mg, 0.822 mmol) and AcOH (21 μL, 0.221mmol) in DCM (3.7 mL) was treated with NaBH(OAc)₃ (198 mg, 0.934 mmol)and stirred overnight at rt. The resulting mixture was diluted with DCM(20 mL) and saturated NaHCO₃ (10 mL). The layers were separated and theaqueous layer was extracted with DCM (2×10 mL). The combined organiclayers were dried over MgSO₄, filtered, and evaporated to dryness. Theresidue was purified by SiO₂ chromatography (DCM/MeOH 0 to 12% gradient)to afford the title compound (178 mg, 0.259 mmol, 69%) as a white foam.

tert-butyl 4-((((1S,3R)-3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)(methyl)amino)methyl)phenylcarbamate

A solution of tert-butyl4-(((1S,3R)-3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexylamino)methyl)phenylcarbamate(178 mg, 0.259 mmol), paraformaldehyde (14 mg, 0.466 mmol) and AcOH (15μL, 0.259 mmol) in DCM (4.3 mL) was treated with NaBH(OAc)₃ (132 mg,0.622 mmol) and stirred 40h at rt. The resulting mixture was dilutedwith DCM (20 mL) and saturated NaHCO₃ (10 mL). The layers were separatedand the aqueous layer was extracted with DCM (2×10 mL). The combinedorganic layers were dried over MgSO₄, filtered, and evaporated todryness. The residue was purified by SiO₂ chromatography (DCM/MeOH 0 to12% gradient) to afford the title compound (96 mg, 0.137 mmol, 53%) as awhite foam.

tert-butyl 4-((((1 S,3R)-3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)(methyl)amino)methyl)phenylcarbamate

A solution of tert-butyl4-((((1S,3R)-3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)(methyl)amino)methyl)phenylcarbamate(96 mg, 0.137 mmol) in dioxane (2.7 mL) was treated with a 5M solutionof NaOH in H₂O (0.55 mL, 2.74 mmol) and heated at 65° C. for 2h. Thecooled mixture was diluted with H₂O (5 mL) and MeTHF (10 mL). The layerswere separated and the aqueous layer was extracted with MeTHF (3×10 mL).The combined organic layers were dried over MgSO4, filtered, andevaporated to dryness. The residue was purified by SiO₂ chromatography(DCM/MeOH 0 to 12% gradient) to afford the title compound (57 mg, 0.102mmol, 74%) as a pale yellow foam.

(1S,3R)—N1-(4-aminobenzyl)-N3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)-N1-methylcyclohexane-1,3-diamine.HCl

A solution of tert-butyl4-((((1S,3R)-3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)(methyl)amino)methyl)phenylcarbamate(57 mg, 0.101 mmol) in DCM (2.0 mL) was treated with a 4M solution ofHCl in dioxane (1.0 mL, 4.06 mmol) and stirred 18h at rt. The resultingmixture was evaporated to dryness to afford the title compound (50 mg,0.101 mmol, 100%) as a bright yellow solid.

Example 22.4-amino-N-((1S,3R)-3-(5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-ylamino)cyclohexyl)benzamide.HCl(Compound 123) tert-butyl(1S,3R)-3-(5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-ylamino)cyclohexylcarbamate

A solution of 3-(2,5-dichloropyrimidin-4-yl)pyrazolo[1,5-a]pyridine(prepared following J. Med. Chem, 2013, 56(17), 7025-7048) (223 mg, 0.84mmol), tert-butyl (1S,3R)-3-aminocyclohexylcarbamate prepared as inexample 3 (200 mg, 0.933 mmol) and DIPEA (171 μL, 0.980 mmol) in NMP(7.8 mL) was heated at 135° C. (mW) for 30 min. The cooled mixture wasdiluted with EtOAc (30 mL), washed with H₂O (10 mL), brine (10 mL),dried over MgSO₄, filtered, and evaporated to dryness. The residue waspurified by SiO₂ chromatography (DCM/MeOH 0 to 12% gradient) to affordthe title compound (280 mg, 0.632 mmol, 68%) as an orange foam.

(1R,3S)—N1-(5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)cyclohexane-1,3-diamine.HCl

A solution of tert-butyl(1S,3R)-3-(5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-ylamino)cyclohexylcarbamate(280 mg, 0.632 mmol) in DCM (4.1 mL) was treated with a 4M solution ofHCl in dioxane (2.04 mL, 8.165 mmol) and stirred 5h at rt. The mixturewas diluted with EtOAc (5 mL) and H₂O (5 mL) and the resultingprecipitate was filtered and washed with EtOAc, affording the titlecompound (142 mg, 0.415 mmol, 66%) as a white solid which was used inthe next step without further purification.

tert-butyl4-((1S,3R)-3-(5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-ylamino)cyclohexylcarbamoyl)phenylcarbamate

A solution of(1R,3S)—N1-(5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)cyclohexane-1,3-diamine.HCl(140 mg, 0.408 mmol) and 4-(tert-butoxycarbonylamino)benzoic acid (116mg, 0.49 mmol) in DMF (4.1 mL) was treated with DIPEA (285 μL, 1.63mmol) and HBTU (232 mg, 0.613 mmol). The resulting mixture was stirredovernight at rt, diluted with EtOAc (30 mL) and saturated NaHCO₃ (10mL). The layers were separated and the organic layer was washed withbrine (10 mL), dried over MgSO₄, filtered, and evaporated to dryness.The residue was purified by SiO₂ chromatography (Hex/EtOAc 0 to 100%gradient) to afford the title compound (229 mg, 0.408 mmol, 100%) as anorange oil.

4-amino-N-((1S,3R)-3-(5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-ylamino)cyclohexyl)benzamide.HCl

A solution of tert-butyl4-((1S,3R)-3-(5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-ylamino)cyclohexylcarbamoyl)phenylcarbamate(229 mg, 0.408 mmol) in DCM (1.0 mL) was treated with a 4M solution ofHCl in dioxane (2.0 mL, 8.0 mmol) and stirred 1h at rt. The resultingmixture was evaporated to dryness and the residue was triturated inEtOAc. The solid was filtered and washed with EtOAc to afford the titlecompound (28 mg, 0.061 mmol, 15%) as a beige solid.

Example 23. Synthesis of5-amino-N-((1S,3R)-3-(5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)picolinamide(Compound 125) 3-(2,5-dichloropyrimidin-4-yl)-1H-indole

To a suspension of3-(2,5-dichloropyrimidin-4-yl)-1-(phenylsulfonyl)-1H-indole (1.50 g,3.71 mmol) in water/1,4-dioxane (62 mL/19 mL) was added an aqueoussolution of NaOH (11 mL, 5M, 55 mmol). The suspension is stirred at 75°C. for 3 h. The reaction was then cooled to room temperature,concentrated under reduced pressure and extracted into DCM (100 mL). TheDCM layer was dried over MgSO₄, filtered, and concentrated to afford thetitle compound as a light yellow oil (0.734 g, 2.78 mmol, 75%) which wasused without any further purification.

3-(2,5-dichloropyrimidin-4-yl)-1-methyl-1H-indole

To a suspension of 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (970 mg,3.67 mmol) in DMF (18.4 mL) at 0° C., sodium hydride in mineral oil(0.220 g, 5.51 mmol, 60% w/w) was added. The reaction was warmed to roomtemperature and stirred for 0.5 h. The reaction was cooled to 0° C. andmethyl iodide (0.834 g, 5.88 mmol) was added. The reaction was warmed toroom temperature and stirred for 12 h. The reaction was poured intoice-water (200 mL) and was extracted with EtOAc (2×50 mL). The organiclayer was washed with brine and directly concentrated to dryness. Thecrude product was then stirred in MTBE (100 mL) for 1h, and a whitesolid is filtered off to afford the title compound as a white-yellowpowder (0.500 g, 1.798 mmol, 49%).

(1S,3R)-3-(Benzyloxycarbonylamino)cyclohexylamino 2,2-dimethylpropionate

To a solution of(1R,3S)-3-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid (preparedfollowing Tetrahedron: Asymmetry 2010 (21), 864-866) (8.77 g, 36.1 mmol)was added Et₃N (5.53 mL, 39.7 mmol) and DPPA (7.7 mL, 36.1 mmol). Theresulting solution was stirred 2h at 110° C. then cooled to 80° C.Benzyl alcohol (4.66 mL, 45.1 mmol) and triethylamine (5.53 mL, 39.7mmol) were added and the mixture was stirred for 20h at 80° C. Thecooled solution was diluted with EtOAc (100 mL) and water (50 mL). Thelayers were separated and the aqueous layer was extracted with EtOAc(2×50 mL). The combined organics were dried (MgSO₄), filtered, andevaporated to dryness. The residue was purified by SiO₂ chromatography(Hex/EtOAc 1 to 100% gradient), to afford the title compound (9.89 g,28.4 mmol, 79%) as a white solid.

tert-butyl (1 S,3R)-3-aminocyclohexylcarbamate

To a degassed solution of(1S,3R)-3-(benzyloxycarbonylamino)cyclohexylamino 2,2-dimethylpropionate(10 g, 28.4 mmol) in EtOH (473 mL) was added 10% w/w Pd/C (450 mg). Thereaction mixture was stirred 5h under H₂ (1 atm). The reaction mixturewas filtered through a pad of celite (EtOH), then the filtrate wasevaporated to dryness to afford the title compound (6.08 g, 28.4 mmol,100%) as a white solid.

tert-butyl (1 S,3R)-3-(5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexylcarbamate

A solution of 3-(2,5-dichloropyrimidin-4-yl)-1-methyl-1H-indole (2.91 g,7.20 mmol), tert-butyl (1S,3R)-3-aminocyclohexylcarbamate (1.24 g, 5.76mmol) and diisopropylethylamine (1.05 mL, 6.05 mmol) in NMP (14.5 mL)was heated 1.5h at 135° C. (mW). The mixture was diluted with EtOAc (200mL), washed with water (50 mL), brine (50 mL), dried (MgSO₄), thenfiltered and evaporated to dryness. The residue was purified by SiO₂chromatography (DCM/EtOAc 0 to 30% gradient) to afford the titlecompound (1.88 g, 3.23 mmol, 56%) as a light yellow foam.

(1R,3S)—N1-(5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)cyclohexane-1,3-diamine.HCl

To a solution of tert-butyl(1S,3R)-3-(5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexylcarbamate(1.88 g, 3.23 mmol) in DCM (16.1 mL) was added a solution of 4 N HCl indioxane (12.11 mL, 48.44 mmol). The resulting mixture was stirred 1.5hat rt before being evaporated to dryness to afford the title compound(1.72 g, 3.10 mmol, 96%) as a light yellow solid which was used in thenext step without further purification.

5-amino-N-((1S,3R)-3-(5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)picolinamide

To a solution of(1R,3S)—N1-(5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)cyclohexane-1,3-diamine.HCl(300 mg, 0.579 mmol) in DMF (4 mL) was added Et₃N (322 μL, 2.315 mmol),5-amino-2-pyridinecarboxylic acid (96 mg, 0.694 mmol), and HBTU (329 mg,0.868 mmol). The mixture was stirred overnight at rt and then dilutedwith EtOAc (20 mL). The mixture was then washed twice with a saturatedsolution of NaHCO₃ (10 mL) followed by brine (5 mL), then dried (MgSO₄),filtered, and evaporated to dryness. The residue was triturated withMTBE and filtered, and the filtrate was evaporated to dryness whichafforded the title compound (282 mg, 0.468 mmol, 81%) as a yellow solid.

Example 24. Synthesis ofN-((1S,3R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)cyclohexyl)-4-(4-(dimethylamino)butanamido)benzamide(Compound 105)

A cooled (−78° C.) solution of4-amino-N-((1S,3R)-3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)benzamide(Compound 102; 300 mg, 0.651 mmol), and DIPEA (340 μL, 1.95 mmol) inTHF/NMP (4.34 mL/0.65 mL) was treated with a 40.84 mg/mL solution of4-(dimethylamino)butanoyl chloride in DCM (4.96 mL, 0.651 mmol). Theresulting mixture was stirred 2h. The resulting mixture was thenevaporated to dryness, and the residue was purified by reverse phasechromatography (C₁₈, H₂O/ACN+0.1% HCO₂H, 5 to 60% gradient) to affordthe title compound (205 mg, 0.357 mmol, 55%) as a light yellow solidafter lyophilisation.

Example 25. Synthesis ofN1-(4-(((1S,3R)-34(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamoyl)phenyl)oxalamide(Compound 113)

4-amino-N-((1S,3R)-3-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)benzamide(Compound 102; 50 mg, 0.11 mmol), oxamic acid (10 mg, 0.11 mmol), HBTU(62 mg, 0.16 mmol) and diisopropylethylamine (38 μL, 0.22 mmol) weredissolved with DMF (1.4 mL) and stirred at room temperature overnight.The resulting mixture was then directly purified by reverse phasechromatography (C₁₈, H₂O/ACN+0.1% HCO₂H, 0 to 60% gradient) to affordthe title compound (6.0 mg, 0.011 mmol, 10%) as a light yellow solidafter lyophilisation.

Example 26. Synthesis of4-amino-N-((1S,3R)-34(5-chloro-4-(1H-indazol-3-yl)pyrimidin-2-yl)amino)cyclohexyl)benzamide(Compound 124) 3-iodo-1H-indazole

To a mixture of 1H-indazole (5 g, 42.32 mmol) and NaOH (3.4 g, 84.6mmol) in DMF (50 mL) was added I₂ (16.1 g, 63.4 mmol) in one portion at25° C. and the mixture was stirred for 6 h. The mixture wasconcentrated, diluted with water (150 mL,) extracted with EA (100 mL*3),and the combined organic phase was washed with saturated brine (200mL*2), dried with anhydrous Na₂SO₄ and concentrated in vacuum. Theresidue was purified by silica gel chromatography to afford the titlecompound (8 g, 77.5%) as white solid.

Tert-butyl 3-iodo-1H-indazole-1-carboxylate

To a mixture of 3-iodo-1H-indazole (8 g, 32.7 mmol) and Boc₂O (8.6 g,39.2 mmol) in MeCN (100 mL) was added NaOH (2.0 g, 49.1 mmol) at 25° C.and the mixture was stirred for 12 h. The mixture was poured into water(150 mL), extracted with EA (50 mL*2), and the combined organic phasewas washed with saturated brine (200 mL*2), dried with anhydrous Na₂SO₄and concentrated in vacuum. The residue was purified by silica gelchromatography to afford the title compound (11.2 g, 97.5%) as whitesolid.

Tert-butyl 3-(trimethylstannyl)-1H-indazole-1-carboxylate

A mixture of tert-butyl 3-iodoindazole-1-carboxylate (4.0 g, 11.6 mmol),Sn₂Me₆ (5.7 g, 17.4 mmol) and Pd(PPh₃)₄ (1.3 g, 1.2 mmol) in toluene (20mL) was heated to 110° C. and stirred for 12 h. The mixture wasconcentrated in vacuum to give title compound (4.43 g, crude), which wasused directly in next step.

Tert-butyl 3-(2,5-dichloropyrimidin-4-yl)-1H-indazole-1-carboxylate

A mixture of tert-butyl 3-trimethylstannylindazole-1-carboxylate (5.0 g,13.1 mmol), 2,4,5-trichloropyrimidine (2.4 g, 13.1 mmol) and Pd(PPh₃)₄(1.5 g, 1.3 mmol) in toluene (100 mL) was heated to 110° C. and stirredfor 12 h. The mixture was concentrated in vacuum, and the residue waspurified by silica gel chromatography to afford the title compound (1.5g, 31.3% for two steps).

Benzyl((1S,3R)-3-((5-chloro-4-(1H-indazol-3-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamate

To a mixture of tert-butyl3-(2,5-dichloropyrimidin-4-yl)indazole-1-carboxylate (1 g, 2.74 mmol),benzyl N-[(1S,3R)-3-aminocyclohexyl]carbamate (0.816 g, 3.3 mmol) andDIPEA (2.1 g, 16.2 mmol) in NMP (20 mL) was stirred at 135° C. for 45min by microwave. The mixture was poured into water (20 mL), extractedwith ethyl acetate (20 mL*2), and the combined organic phase was washedwith saturated brine (20 mL*3), dried with anhydrous Na₂SO₄ andconcentrated in vacuum. The residue was purified by pre-HPLC to affordthe title compound (0.75 g, 57.3%) as yellow solid.

5-chloro-N-((1R,3S)-3-(piperazin-1-yl)cyclohexyl)-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine

To a mixture of benzylN-[(1S,3R)-3-[[5-chloro-4-(1H-indazol-3-yl)pyrimidin-2-yl]amino]cyclohexyl]carbamate(0.7 g, 1.5 mmol) in DCM (10 mL) was added TMSI (1.47 g, 7.3 mmol) at25° C., the mixture was stirred for 12 h. The mixture was poured intowater (20 mL), extracted with ethyl acetate (10 mL*2), and the aqueousphase was concentrated in vacuum to afford the title compound (0.32 g,crude)

Tert-butyl(4-(((1S,3R)-3-((5-chloro-4-(1H-indazol-3-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamoyl)phenyl)carbamate

To a mixture of(1R,3S)—N1-[5-chloro-4-(1H-indazol-3-yl)pyrimidin-2-yl]cyclohexane-1,3-diamine(300 mg, 0.9 mmol) and 4-(tert-butoxycarbonylamino)benzoic acid (249.1mg, 1.1 mmol) in DMF (10 mL) was added HATU (499.1 mg, 1.3 mmol) andDIPEA (226.2 mg, 1.8 mmol) at 30° C. and the mixture was stirred for 12h. The mixture was poured into water (50 mL), extracted with EA (20mL*2), and the combined organic phase was washed with saturated brine(50 mL*2), dried with anhydrous Na₂SO₄, and concentrated in vacuum. Theresidue was purified by silica gel chromatography to afford the titlecompound (200 mg, 25.8% for two steps).

4-amino-N-((1S,3R)-3-((5-chloro-4-(1H-indazol-3-yl)pyrimidin-2-yl)amino)cyclohexyl)benzamide(Compound 124)

A mixture of tert-butylN-[4-[[(1S,3R)-3-[[5-chloro-4-(1H-indazol-3-yl)pyrimidin-2-yl]amino]cyclohexyl]carbamoyl]phenyl]carbamate(200 mg, 0.35 mmol) in HCl/MeOH (20 mL) was stirred at 25° C. for 2 h.The mixture was concentrated in vacuum to afford the title compound (150mg, crude). LCMS: ET1741-37-P2B (M+H⁺): 462.2 @ 0.748 min (5-95% ACN inH₂O, 1.5 min).

Example 27. Synthesis of4-amino-N-((1S,3R)-34(5-chloro-4-(2-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)cyclohexyl)benzamide(Compound 126) 3-iodo-2-methyl-1H-indole

To a mixture of 2-methyl-1H-indole (20 g, 152.47 mmol) and KOH (21.39 g,381.18 mmol) in DMF (200 mL) was added I₂(38.7 g, 152.47 mmol) at 30° C.and the mixture was stirred for 12 h. The mixture was poured into water,extracted with EA, and the organic layer was dried over Na₂SO₄ andconcentrated and the residue was purified by column (PE:EA=15:1) toafford the title compound (25 g, 63.8%).

3-iodo-2-methyl-1-(phenylsulfonyl)-1H-indole

To a solution of 3-iodo-2-methyl-1H-indole (25 g, 97.25 mmol) in DMF(320 mL) was added NaH (4.67 g, 116.70 mmol) at 0° C. and the mixturewas stirred at 30° C. for 1 h. Then benzenesulfonyl chloride (18.04 g,102.11 mmol) was added and the mixture was stirred at 30° C. for 8 h.The mixture was poured into water, extracted with EA, and the organiclayer was dried over Na₂SO₄ and concentrated. The residue was purifiedby column (PE:EA=20:1) to afford the title compound (28 g, 72.8%).

3-(2,5-dichloropyrimidin-4-yl)-2-methyl-1-(phenylsulfonyl)-1H-indole

To a solution of 3-iodo-2-methyl-1-(phenylsulfonyl)-1H-indole (20 g,50.35 mmol) in THF (400 mL) was added i-PrMgCl⁻LiCl (14.63 g, 100.70mmol) at −78° C. and the mixture was stirred under N₂ for 1 h. Then2,5-dichloropyrimidine (15 g, 100.70 mmol) was added at −78° C., thereaction was stirred at 30° C. for 3 h, then H₂O (2.09 g, 115.80 mmol)in THF (10 mL) was added at 0° C., finally DDQ (22.86 g, 100.70 mmol)was added, and the final mixture was stirred at 30° C. for 6 h. Themixture concentrated, diluted with water, extracted with EA, and theorganic layer was concentrated. The residue was purified by column(PE:EA=10:1) to afford the title compound (6 g, 28.5%).

Benzyl ((1 S,3R)-3-((5-chloro-4-(2-methyl-1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamate

A mixture of3-(2,5-dichloropyrimidin-4-yl)-2-methyl-1-(phenylsulfonyl)-1H-indole(5.0 g, 11.95 mmol), benzyl ((1S,3R)-3-aminocyclohexyl)carbamate (3.4 g,11.95 mmol) and DIEA (5.41 g, 41.83 mmol) in DMF (30 mL) and EtOH (30mL) was stirred at 120° C. for 12 h. The mixture was concentrated, andthe residue was purified by column (PE:EA=4:1) to afford the titlecompound (5.1 g, 67.7%).

(1R,3S)—N1-(5-chloro-4-(2-methyl-1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)cyclohexane-1,3-diamine

A mixture of benzyl((1S,3R)-3-((5-chloro-4-(2-methyl-1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamate(5.0 g, 7.93 mmol) and Pd/C (0.80 g) in MeOH (100 mL) was stirred at 25°C. for 24 h under H₂ (40 psi). The mixture was filtered and concentratedto afford the title compound (2.7 g, crude).

Tert-butyl (4-(((1 S,3R)-3-((5-chloro-4-(2-methyl-1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamoyl)phenyl)carbamate

A mixture of(1R,3S)—N1-(5-chloro-4-(2-methyl-1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)cyclohexane-1,3-diaminetrifluoromethanesulfonate(1.5 g, 3.02 mmol), 4-((tert-butoxycarbonyl)amino)benzoic acid (0.72 g,3.02 mol), HATU (1.21 g, 3.18 mmol) and DIEA (0.47 g, 3.63 mmol) in DMF(30 mL) was stirred at 30° C. for 6 h. The reaction solution was pouredinto water, extracted with EA, and the organic layer was dried andconcentrated to afford the title compound (2.0, crude).

Tert-butyl(4-(((1S,3R)-34(5-chloro-4-(2-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamoyl)phenyl)carbamate

A mixture of tert-butyl(4-(((1S,3R)-3-((5-chloro-4-(2-methyl-1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamoyl)phenyl)carbamate(1.8 g, 2.52 mmol), K₂CO₃ (6.97 g, 0.44 mmol) and morpholine (0.44 g,5.04 mmol) in EtOH (50 mL) was stirred at 70° C. for 12 h. The mixturewas filtered, and the filtrate was concentrated to provide a residuethat was purified by HPLC (acid condition) to afford the title compound(0.63 g, 43.6%).

4-amino-N-((1S,3R)-3-((5-chloro-4-(2-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)cyclohexyl)benzamide(Compound 126)

To a solution of tert-butyl(4-(((1S,3R)-3-((5-chloro-4-(2-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)cyclohexyl)carbamoyl)phenyl)carbamate(700 mg, 1.22 mmol) in EA (5 mL) was added into a solution of HCl/EA (25mL) and the mixture was stirred at 30° C. for 12 h. The mixture wasconcentrated to afford the title compound (500 mg, 80.1%).

Example 28. Synthesis of4-amino-3-fluoro-N-[(1S,3R)-3-[[4-(1H-indazol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-1-methyl-cyclohexyl]benzamide(Compound 127) 2-(2-benzhydrylidenehydrazino)benzonitrile

To a mixture of 2-bromobenzonitrile (27 g, 148 mmol), Cs₂CO₃ (68 g, 208mmol) 2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (5.5 g, 8.9 mmol) anddiphenylmethanone hydrazone (32 g, 163 mmol) in toluene (100 mL) wasadded Pd(OAc)₂ (1.7 g, 7.4 mmol) under N₂. The mixture was heated to100° C. and stirred for 12 h, then cooled to 25° C. and filtered. Thefiltrate was concentrated to afford the title compound (54 g, crude).

2-[(benzhydrylideneamino)-benzyl-amino]benzonitrile

To a mixture of 2-(2-benzhydrylidenehydrazino)benzonitrile (54 g, 182mmol) and (bromomethyl)benzene (47 g, 272 mmol) in DMF (200 mL) wasadded K₂CO₃ (50 g, 363 mmol) in one portion at 25° C. under N₂. Themixture was stirred at 25° C. for 12 h, then filtered. The filtrate wasconcentrated and purified by re-crystallization from EA (150 mL) and PE(500 mL) to afford the title compound (50 g, crude) as a yellow solid.

1-benzyl-1H-indazol-3-amine

To a solution of 2-[(benzhydrylideneamino)-benzyl-amino]benzonitrile (21g, 54 mmol) in MeOH (120 mL) was added 4-methylbenzenesulfonic acid (23g, 135 mmol) in one portion at 25° C. under N₂. The mixture was heatedto 80° C. and stirred for 12 h. The mixture was cooled to 25° C. andconcentrated. The residue was dissolved with water. The aqueous phasewas extracted with EA (150 mL*3). The combined organic phase were washedwith saturated brine (150 mL), dried with anhydrous Na₂SO₄, filtered andconcentrated in vacuum. The residue was purified by silica gelchromatography (PE/EA=5/1) to afford the title compound (10 g, 74%) as ayellow solid.

1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole

To a mixture of 1-benzylindazol-3-amine (6.5 g, 29 mmol) and4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(10.4 g, 41 mmol) in MeCN (100 mL) was added tert-butyl nitrite (3.3 g,32 mmol) in one portion at 25° C. under N₂. The mixture was heated to85° C. and stirred for 1.5 h. The mixture was purified by prep-HPLC(TFA) to afford the title compound (2.6 g, 22%, TFA) as a yellow solid.

1-benzyl-3-[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]indazole

To a mixture of (1-benzylindazol-3-yl)boronic acid (1 g, 2.7 mmol, TFA)and 2,4-dichloro-5-(trifluoromethyl)pyrimidine (889 mg, 4.1 mmol) in H₂O(4 mL) and 1,2-dimethoxyethane (20 mL) was added Pd(dppf)Cl₂ (100 mg,0.14 mmol) and TEA (553 mg, 5.5 mmol) under N₂. The mixture was heatedto 65° C. and stirred for 5 h. The reaction mixture was concentratedunder reduced pressure. The residue was diluted with water (30 mL) andextracted with DCM (30 mL*2). The combined organic layers were washedwith brine (50 mL), dried over Na₂SO₄, filtered, concentrated andpurified by column chromatography (SiO₂, PE/EA=40/1) to provide titlecompound (0.9 g, 76%) as a white solid.

Benzyl-((1 S,3R)-3-((4-(1-benzyl-3a,7a-dihydro-1H-indazol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)cyclohexyl)carbamate

To a mixture of1-benzyl-3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-indazole (700mg, 1.8 mmol) and benzyl ((1S,3R)-3-aminocyclohexyl)carbamate (667 mg,2.34 mmol HCl) in NMP (10 mL) was added DIPEA (698 mg, 5.4 mmol). Themixture was heated to 150° C. and stirred for 3 h, then cooled to 25° C.and poured into water (30 mL). The aqueous phase was filtered. The cakewas dried under reduced pressure to afford the title compound (800 mg,49%) as a white solid.

(1R,3S)—N1-[4-(1-benzylindazol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]cyclohexane-1,3-diamine

To a solution of benzylN-[(1S,3R)-3-[[4-(1-benzyl-3a,7a-dihydroindazol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]cyclohexyl]carbamate(800 mg, 1.33 mmol) in THF (30 mL) was added Pd/C (2 g) under N₂. Thesuspension was degassed under vacuum and purged with H₂ several times.The reaction was stirred under H₂ (50 psi) at 20° C. for 24 h. Thereaction mixture was filtered and concentrated under reduced pressure togive the title compound (500 mg, crude) as a white solid.

(1R,3S)—N1-[4-(1H-indazol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]cyclohexane-1,3-diamine

To a solution of(1R,3S)—N1-[4-(1-benzylindazol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]cyclohexane-1,3-diamine(500 mg, 1.07 mmol) in DMSO (2 mL) and THF (2 mL) was added t-BuOK (960mg, 8.56 mmol) under N₂. Then oxygen was bubbled into the reaction at20° C. for 2 h. The reaction mixture was quenched by addition of TFA topH=6. The mixture was purified by prep-HPLC (TFA) to give the titlecompound (400 mg, 76%, TFA) as a yellow solid.

4-amino-3-fluoro-N-[(1S,3R)-3-[[4-(1H-indazol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-1-methyl-cyclohexyl]benzamide(Compound 127)

To a mixture of(1S,3R)—N3-[4-(1H-indazol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]-1-methy1-cyclohexane-1,3-diamine (60 mg, 102 μmol, TFA) and4-amino-3-fluoro-benzoic acid (14.6 mg, 92 μmol) in DMF (2 mL) was addedDIEA (68 mg, 512 μmol) and HBTU (39.6 mg, 102 μmol) under N₂. Themixture was stirred at 20° C. for 12 h. The mixture was purified byprep-HPLC (HCl) to provide the title compound (7.3 mg, 13%, HCl) as ayellow solid. LCMS: (M+H⁺): 528.3 @ 3.006 min (10-80% ACN in H₂O, 4.5min). ¹H NMR: (MeOD, 400 MHz): δ 8.64 (s, 1H), 8.45 (s, 1H), 8.67-8.51(m, 4H), 7.37 (s, 1H), 7.14 (s, 1H), 4.57-4.50 (m, 1H), 2.65 (s, 1H),2.16 (s, 1H), 2.04-1.95 (m, 3H), 1.91-1.52 (m, 6H).

Example 29. Synthesis of4-amino-N-((1S,3R)-34(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-1-methylcyclohexyl)benzamide (Compound 128)tert-butyl(4-(((1S,3R)-34(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-1-methylcyclohexyl)carbamoyl)phenyl)carbamate

To a solution of(1R,3S)—N1-(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)-3-methyl-cyclohexane-1,3-diamine(1.0 g, 2.81 mmol), and 4-((tert-butoxycarbonyl)amino)benzoic acid (0.73g, 3.09 mmol) in DMF (20 mL) was added HBTU (1.4 g, 3.65 mmol) and DIPEA(0.54 g, 4.22 mmol). The mixture was stirred at 20° C. for 12 h, thendiluted with water (30 mL) and extracted with EA (50 mL*3). The organiclayer was combined, dried over Na₂SO₄, filtered, and concentrated. Theresidue was purified by column chromatography (SiO₂, PE/EA=5:1 to 2:1)to give title compound (1.5 g, 92.8%)

4-amino-N-((1S,3R)-34(5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-1-methylcyclohexyl)benzamide(Compound 128)

To a solution oftert-butyl(4-(((1S,3R)-3-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-1-methylcyclohexyl)carbamoyl)phenyl)carbamate (100 mg, 0.17 mmol)was added HCl/MeOH (50 mL), and the mixture was stirred at 15° C. for 12h. The reaction mixture was concentrated, and the residue was purifiedby prep-HPLC (HCl) to afford the title compound (40 mg, 48.4%). LCMS:M+H⁺: 475.3@ 2.472 min (10-80% ACN in H₂O, 4.5 min). ¹H NMR (MeOD, 400MHz): δ 8.67 (d, J=7.53 Hz, 1H), 8.48 (br. s., 1H), 8.26 (br. s., 1H),7.53 (d, J=8.53 Hz, 2H), 7.23-7.12 (m, 3H), 6.51 (d, J=8.53 Hz, 2H),5.53 (br. s., 2H), 4.11 (br. s., 1H), 2.34 (br. s., 2H), 1.94 (d,J=12.05 Hz, 2H), 1.75 (d, J=8.03 Hz, 3H), 1.52 (br. s., 4H), 1.31 (d,J=11.54 Hz, 1H).

Example 30. Synthesis of3-chloro-4-[[4-(dimethylamino)-3-hydroxy-butanoyl]amino]-N-[(1S,3R)-3-[[4-(1H-indazol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-1-methyl-cyclohexyl]benzamide(Compound 129) 4-amino-3-chloro-N-[(1 S,3R)-3-[[4-(1H-indazol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-1-methyl-cyclohexyl]benzamide

A solution of 4-amino-3-chloro-benzoic acid (68.03 mg, 396.49 mol), HATU(158.30 mg, 416.31 μmol) and DIPEA (102.48 mg, 792.98 mol) in DMF (10mL) was stirred at 25° C. for 0.5 h, then(1S,3R)—N3-[4-(1H-indazol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]-1-methyl-cyclohexane-1,3-diamine(200 mg, 396.49 mol, TFA) was added. The mixture was stirred at 25° C.for 11.5 h, then diluted with water (60 mL). The aqueous phase wasextracted with ethyl acetate (50 mL*3), and the combined organic phasewas washed with brine (50 mL*2), dried over anhydrous Na₂SO₄, filtered,and concentrated under vacuum. The residue was purified by silica gelchromatography (DCM:MeOH=120:1-100:1-80:1) to afford the title compound(170 mg, 78%) as white solid.

3-chloro-4-[[4-(dimethylamino)-3-hydroxy-butanoyl]amino]-N-[(1S,3R)-3-[[4-(1H-indazol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-1-methyl-cyclohexyl]benzamide(Compound 129)

To a stirred solution of (E)-4-(dimethylamino)but-2-enoic acid (121.04mg, 735.35 mol) in DCM (2 mL) was added oxalyl dichloride (93.33 mg,735.35 mol) at 0° C., followed by DMF (4.9 mg, 0.14 mol), then thereaction mixture was stirred at 0° C. for 1 h. The solution was thenadded to a mixture of4-amino-3-chloro-N-[(1S,3R)-3-[[4-(1H-indazol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-1-methyl-cyclohexyl]benzamide(80 mg, 147.07 μmol) and pyridine (34.90 mg, 441.21 mol) in THF (3 mL)and NMP (3 mL). After the addition the mixture was stirred at 25° C. for11 h, at which point the mixture was concentrated under vacuum. Theresidue was purified by prep-HPLC (neutral) to afford the title compound(28.6 mg, 28%) as white solid. LCMS: ET3428-395-P1A, M+H⁺: 673.3@2.576min (10-80% ACN in H₂O, 4.5 min). ¹H NMR ET3428-395-P1A (MeOD, 400 MHz)δ 8.61 (s, 1H), 7.75 (s, 1H), 7.64-7.63 (m, 2H), 7.51 (s, 1H), 7.44-7.41(m, 1H), 7.24 (s, 1H), 6.91 (s, 1H), 4.8 (m, 2H), 4.27 (s, 2H), 2.86 (s,6H), 2.64-2.60 (m, 3H), 2.08-2.01 (m, 1H), 1.99-1.91 (m, 1H), 1.85-1.81(m, 3H), 1.66-1.63 (m, 1H), 1.57 (s, 3H), 1.45-1.42 (m, 1H).

Example 31. Synthesis of3-fluoro-4-(methylamino)-N-[(1S,3R)-1-methyl-3-[[4-(7-methyl-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]cyclohexyl]benzamide(Compound 130) Benzyl N-[(1 S,3R)-1-methyl-3-[[4-(7-methyl-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]cyclohexyl]carbamate

A solution of3-[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]-7-methyl-1H-indole (4.7g, 14.93 mmol), benzyl N-[(1S,3R)-3-amino-1-methyl-cyclohexyl]carbamate(3.92 g, 14.93 mmol) and DIEA (4.82 g, 37.32 mmol) in NMP (40 mL) wasstirred at 140° C. for 3 h. The mixture was diluted with water (100 mL),and the aqueous phase was extracted with ethyl acetate (50 mL*3). Thecombined organic phase was washed with brine (50 mL*3), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue waspurified by silica gel chromatography (PE:EA=10:1-5:1-3:1) to give thetitle compound (8 g, 92%) as a yellow solid.

(1S,3R)-1-methyl-N3-[4-(7-methyl-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]cyclohexane-1,3-diamine

A solution of benzylN-[(1S,3R)-1-methyl-3-[[4-(7-methyl-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]cyclohexyl]carbamate(6 g, 11.16 mmol), Pd/C (2 g, 10% wet) in EA (80 mL) was stirred at 25°C. under H₂ (50 psi) for 12 h. The mixture was filtered through a celitepad and the filtrate was concentrated under vacuum to give the titlecompound (5 g, crude) as a white solid and used directly in next stepwithout further purification.

4-amino-3-fluoro-N-[(1S,3R)-1-methyl-3-[[4-(7-methyl-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]cyclohexyl]benzamide

A solution of(1S,3R)-1-methyl-N3-[4-(7-methyl-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]cyclohexane-1,3-diamine(600 mg, 1.49 mmol), 4-amino-3-fluorobenzoic acid (231.14 mg, 1.49mmol), HATU (623.20 mg, 1.64 mmol) and DIPEA (288.85 mg, 2.24 mmol) inDMF (15 mL) was stirred at 25° C. for 12 h. The mixture was diluted withwater (50 mL), and the aqueous phase was extracted with ethyl acetate(50 mL*3). The combined organic phase was washed with brine (20 mL*3),dried over anhydrous Na₂SO₄, filtered and concentrated in vacuum. Theresidue was purified by silica gel chromatography(DCM:MeOH=120:1-100:1-70:1) to give the title compound (600 mg, 69%) asa yellow solid.

3-fluoro-4-(methylamino)-N-[(1S,3R)-1-methyl-3-[[4-(7-methyl-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]cyclohexyl]benzamide(Compound 130)

A solution of4-amino-3-fluoro-N-[(1S,3R)-1-methyl-3-[[4-(7-methyl-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]cyclohexyl]benzamide(250 mg, 462.49 μmol) and methyl trifluoromethanesulfonate (60.72 mg,369.99 μmol) in HFIP (10 mL) was stirred at 30° C. for 2 h. The reactionwas quenched with HCl (1 N, 30 mL) and extracted with EA (30 mL*3), thenthe combined organic phase was dried over anhydrous Na₂SO₄, filtered,and concentrated under vacuum. The residue was purified by prep-TLC(PE:EA=2:1) and prep-HPLC (TFA). The solution of prep-HPLC was basedwith sat. NaHCO₃ (10 mL) and extracted with ethyl acetate (30 mL*3). Thecombined organic phase was dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuum to give title compound (50 mg, 19%) as yellowoil. The residue (40 mg) was purified by prep-HPLC (HCl) to give3-fluoro-4-(methylamino)-N-[(1S,3R)-1-methyl-3-[[4-(7-methyl-1H-indol-3-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]cyclohexyl]benzamide(27.1 mg, HCl salt). LCMS: M+H⁺: 555.3 @3.173 min (10-80% ACN in H₂O,4.5 min). ¹H NMR (MeOD, 400 MHz) δ 8.47 (s, 1H), 8.37 (s, 1H), 8.18 (s,1H), 7.49 (d, J=7.6 Hz, 1H), 7.40 (d, J=12.8 Hz, 1H), 7.19-7.13 (m, 2H),6.67 (s, 1H), 4.55-4.51 (m, 1H), 2.85 (s, 3H), 2.56 (s, 3H), 2.16-2.03(m, 2H), 1.94-1.87 (m, 3H), 1.74-1.70 (m, 1H), 1.67-1.46 (m, 4H), 1.28(s, 1H).

Example 32. CDK7 Kinase Activity

Compounds of the invention were assayed for CDK7 activity at LifeTechnologies™ (Grand Island, N.Y.) using their commercially availableAdapta® kinase assay services. Test compounds were tested atconcentrations ranging from 10 μM down to 0.514 nM in a series of 3-foldserial dilutions. Details of this assay, including substrates used, areavailable on the Life Technologies web site(http://www.lifetechnologies.com/us/en/home/life-science/drug-discovery/target-and-lead-identification-and-validation/kinasebiology/kinase-activity-assays.html).The results of the assay are shown below in Table 3 where “A” representsa calculated IC₅₀ of less than 100 nM; “B” represents a calculated IC₅₀of between 100 nM and 1 μM; and “C” represents a calculated IC₅₀ ofgreater than 1 μM.

TABLE 3 CDK7 Inhibitory Activity of Selected Compounds of the Invention.CDK7 Compound Inhibition No. (IC₅₀) 100 C 101 A 102 B 103 B 104 B 105 A106 A 107 A 108 C 109 B 110 B 111 B 112 B 113 B 114 C

Example 33. Inhibition of Cell Proliferation

Representative compounds of the invention were tested at differentconcentrations (from 10 μM to 316 pM; 0.5 log serial dilutions) fortheir ability to inhibit the proliferation of Jurkat cells. Known CDKinhibitors flavopiridol and triptolide were used as positive controls.Cells were grown in RPMI 1640+10% FBS+1% Glutamax. The cells weresupplemented with FBS (Life Technologies) and 100 U mL⁻¹ penicillin, 100μg·mL⁻¹ streptomycin (Invitrogen) and cultured at 37° C. in a humidifiedchamber in the presence of 5% CO₂. Proliferation assays were conductedover a 72 hour time period. CellTiter-Glo® (Promega Corporation,Madison, Wis. USA) was used to assess the anti-proliferative effects ofthe compounds following manufacturer's directions and utilizing thereagents supplied with the CellTiter-Glo® kit. In this table, “A”represents an IC₅₀ of less than 500 nM; “B” an IC₅₀ of between 500 nMand 5 μM; and “C” an IC₅₀ of greater than 5 μM.

TABLE 4 Inhibition of Proliferation of Jurkat Cells by Compounds of theInvention. Compound Jurkat No. IC₅₀ 101 B 102 C 103 C 104 C 105 B 106 C107 A 108 C 109 B 111 C 112 B 113 B

EQUIVALENTS AND SCOPE

In the claims articles such as “a,” “an,” and “the” may mean one or morethan one unless indicated to the contrary or otherwise evident from thecontext. Claims or descriptions that include “or” between one or moremembers of a group are considered satisfied if one, more than one, orall of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention includes embodiments in which more than one or all of thegroup members are present in, employed in, or otherwise relevant to agiven product or process.

Furthermore, the invention encompasses all variations, combinations, andpermutations in which one or more limitations, elements, clauses, anddescriptive terms from one or more of the listed claims are introducedinto another claim. For example, any claim that is dependent on anotherclaim can be modified to include one or more limitations found in anyother claim that is dependent on the same base claim. Where elements arepresented as lists, e.g., in Markush group format, each subgroup of theelements is also disclosed, and any element(s) can be removed from thegroup. It should it be understood that, in general, where the invention,or aspects of the invention, is/are referred to as comprising particularelements and/or features, certain embodiments of the invention oraspects of the invention consist, or consist essentially of, suchelements and/or features. For purposes of simplicity, those embodimentshave not been specifically set forth in haec verba herein. It is alsonoted that the terms “comprising” and “containing” are intended to beopen and permits the inclusion of additional elements or steps. Whereranges are given, endpoints are included. Furthermore, unless otherwiseindicated or otherwise evident from the context and understanding of oneof ordinary skill in the art, values that are expressed as ranges canassume any specific value or subrange within the stated ranges indifferent embodiments of the invention, to the tenth of the unit of thelower limit of the range, unless the context clearly dictates otherwise.

This application refers to various issued patents, published patentapplications, journal articles, and other publications, all of which areincorporated herein by reference. If there is a conflict between any ofthe incorporated references and the instant specification, thespecification shall control. In addition, any particular embodiment ofthe present invention that falls within the prior art may be explicitlyexcluded from any one or more of the claims. Because such embodimentsare deemed to be known to one of ordinary skill in the art, they may beexcluded even if the exclusion is not set forth explicitly herein. Anyparticular embodiment of the invention can be excluded from any claim,for any reason, whether or not related to the existence of prior art.

Those skilled in the art will recognize or be able to ascertain using nomore than routine experimentation many equivalents to the specificembodiments described herein. The scope of the present embodimentsdescribed herein is not intended to be limited to the above Description,but rather is as set forth in the appended claims. Those of ordinaryskill in the art will appreciate that various changes and modificationsto this description may be made without departing from the spirit orscope of the present invention, as defined in the following claims.

1. A compound having the structural formula I:

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, orstereoisomer thereof, wherein: ring A is an optionally substitutedheteroaryl ring of any one of the Formulae (i-1)-(i-6):

wherein: each instance of V¹, V², V³, V⁴, V⁵, V⁶, V⁷, V⁸, V⁹, V¹⁰, V¹¹,V¹², V¹³, V¹⁴ and V¹⁵ is independently O, S, N, N(R^(A1)), C, orC(R^(A2)); each instance of R^(A1) is independently selected fromhydrogen, deuterium, optionally substituted acyl, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, and optionally substituted heteroaryl; eachinstance of R^(A2) is independently selected from hydrogen, deuterium,halogen, —CN, optionally substituted acyl, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl,—OR^(A2a), —N(R^(A2a))₂, and —SR^(A2a), wherein each occurrence ofR^(A2a) is independently selected from hydrogen, optionally substitutedacyl, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl, andoptionally substituted heteroaryl, or any two R^(A1), any two R^(A2), orone R^(A1) and one R^(A2) are joined to form an optionally substitutedcarbocyclic, optionally substituted heterocyclic, optionally substitutedaryl, or optionally substituted heteroaryl ring; each X is independentlyselected from N and CH, wherein at least one X is N; W is selected fromN and C(R^(1a)); each of R^(1a), if present, and R^(1b) is independentlyselected from hydrogen, deuterium, halogen, optionally substituted acyl,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, —CN, —OR^(B1a), —N(R^(B1a))₂, and —SR^(B1a),wherein each occurrence of R^(B1a) is independently selected fromhydrogen, optionally substituted acyl, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, and optionally substituted heteroaryl, orR^(1a) and R^(1b) are joined to form an optionally substitutedcarbocyclic, optionally substituted heterocyclic, optionally substitutedaryl, or optionally substituted heteroaryl ring; R² is an optionallysubstituted C₁-C₄ alkylene or an optionally substituted C₂-C₄ alkenyleneor alkynylene, wherein one or more methylene units of the alkylene,alkenylene or alkynylene are optionally and independently replaced with—O—, —S—, or —N(R⁷)—; R³ is selected from a bond, an optionallysubstituted C₁-C₄ alkylene, and an optionally substituted C₂-C₄alkenylene or alkynylene, wherein one or more methylene units of thealkylene, alkenylene or alkynylene is optionally and independentlyreplaced with —O—, —S—, —N(R⁷)—, or —S(O)₂—; R⁴ is selected from —C₁-C₈alkyl, —O—C₁-C₈ alkyl, —NH₂, —NH(C₁-C₈ alkyl), and —N(C₁-C₈ alkyl)₂,wherein each alkyl in R⁴ is optionally and independently substituted.each R⁵, if present, is independently selected from deuterium, halogen,optionally substituted acyl, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, —OR^(D1),—N(R^(D1))₂, and —SR^(D1), wherein each occurrence of R^(D1) isindependently selected from hydrogen, optionally substituted acyl,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, and optionally substituted aryl, optionallysubstituted heteroaryl; each R⁶, if present, is independently selectedfrom the group consisting of deuterium, halogen, optionally substitutedacyl, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, ═O, —CN, —OR^(C1), —N(R^(C1))₂, and—SR^(C1), wherein each occurrence of R^(C1) is independently selectedfrom the group consisting of hydrogen, optionally substituted acyl,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, a nitrogen protecting group when attached to anitrogen atom, an oxygen protecting group when attached to an oxygenatom, and a sulfur protecting group when attached to a sulfur atom, ortwo R^(C1) groups are joined to form an optionally substitutedheterocyclic ring; or two R⁶ are taken together to form a first 5-7membered optionally substituted, heterocyclyl or carbocyclyl ring fusedto the ring to which the R⁶ are bound; wherein two substituents on thesubstituted heterocyclyl or carbocyclyl ring, or one substituent on thesubstituted heterocyclyl or carbocyclyl ring and a third R⁶ may be takentogether with the atoms to which they are bound to form a secondoptionally substituted, heterocyclyl or carbocyclyl ring fused to thering to the first optionally substituted, heterocyclyl or carbocyclylring and/or the ring to which the third R⁶ is bound; each R⁷ isindependently selected from hydrogen, and optionally substituted —C₁-C₆alkyl; n is 0, 1, 2, 3, 4, 5 or 6; and p is 0, 1, 2 or 3, wherein thecompound is other than

and stereoisomers and enantiomers thereof.
 2. The compound of claim 1,wherein ring A is selected from:


3. The compound of claim 2, wherein, ring A is selected from:


4. The compound of claim 1, wherein each X is N.
 5. The compound ofclaim 1, wherein W is C(R^(1a)).
 6. The compound of claim 5, whereinR^(1a) is selected from selected from hydrogen, halo, —OH, —C₁-C₃ alkyl,halo-substituted —C₁-C₃ alkyl, —O—C₁-C₃ alkyl, halo-substituted —O—C₁-C₃alkyl, —CN, —NH₂, —NH(C₁-C₃ alkyl), —N(C₁-C₃ alkyl)₂, and C₃-C₆cycloalkyl.
 7. The compound of claim 6, wherein R^(1a) is selected fromhydrogen, chloro, fluoro, —CN, —CF₃, and cyclopropyl.
 8. The compound ofclaim 1, wherein R^(1b) is hydrogen.
 9. The compound of claim 1, whereinR² is selected from —NH—; —N(C₁-C₃ alkyl)-; —NH—CH₂—*; and C₁-C₂alkylene optionally substituted with 1 to 4 substituents independentlyselected from halo, —OH, —C₁-C₃ alkyl, halo-substituted —C₁-C₃ alkyl,—O—C₁-C₃ alkyl, halo-substituted —O—C₁-C₃ alkyl, —CN, —NH₂, —NH(C₁-C₃alkyl), —N(C₁-C₃ alkyl)₂, wherein “*” represents a portion of R² boundto a cyclohexyl ring.
 10. The compound of claim 9, wherein R² is —NH—.11. The compound of claim 1, wherein R³ is selected from †—NH—C(O)—,†—C(O)—NH—, †—NH—S(O)₂—, †—NH—CH(CF₃)—, and —N(CH₃)—CH₂—, wherein “†”represents a portion of R³ bound to a cyclohexyl ring.
 12. The compoundof claim 1, wherein R⁴ is selected from —NH₂, —NH—C(O)—(CH₂)₃—N(CH₃)₂,—NH—C(O)—CH₂—CH(OH)—CH₂—N(CH₃)₂, —NH—CH₃, and —NH—C(O)—C(O)—NH₂.
 13. Thecompound of claim 1, wherein R⁵ is absent or each R⁵ is independentlyselected from fluoro, chloro and morpholin-4-yl.
 14. The compound ofclaim 1, wherein R⁶ or each R⁶ is independently selected from —OH,fluoro, and methyl, or two or three R⁶ are taken together with thecarbon atoms in the cyclohexyl ring depicted in Formula I to form:

wherein “2” represents a portion of the ring bound to R², and “3”represents a portion of the ring bound to R³.
 15. The compound of claim1, having the Formula (Ia):


16. The compound of claim 1, having the Formula (Ib):

wherein: ring A is selected from

R^(1a) is selected from hydrogen, chloro, fluoro, —CN, —CF₃, andcyclopropyl; R³ is selected from †—NH—C(O)—, †—C(O)—NH—, †—NH—S(O)₂—,†—NH—CH(CF₃)—, and —N(CH₃)—CH₂—, wherein “†” represents a portion of R³bound to a cyclohexyl ring; R⁴ is selected from —NH₂,—NH—C(O)—(CH₂)₃—N(CH₃)₂, —NH—C(O)—CH₂—CH(OH)—CH₂—N(CH₃)₂, —NH—CH₃, and—NH—C(O)—C(O)—NH₂; R⁵ is absent, or each R⁵ is independently selectedfrom fluoro, chloro, and morpholin-4-yl; and R⁶ is absent, or each R⁶ isindependently selected from —OH, halo, and C₁-C₃ alkyl; or two or threeR⁶ bound to separate carbon atoms are taken together with the carbonatoms to form:

wherein “2” represents a portion of the ring bound to R², and “3”represents a portion of the ring bound to R³.
 17. The compound of claim1, selected from any one of Compounds 100-130.
 18. A pharmaceuticalcomposition comprising: a) a compound of Formula (I):

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, orstereoisomer thereof, wherein: ring A is an optionally substitutedheteroaryl ring of any one of the Formulae (i-1)-(i-6):

wherein: each instance of V¹, V², V³, V⁴, V⁵, V⁶, V⁷, V⁸, V⁹, V¹⁰, V¹¹,V¹², V¹³, V¹⁴ and V¹⁵ is independently O, S, N, N(R^(A1)), C, orC(R^(A2)); each instance of R^(A1) is independently selected fromhydrogen, deuterium, optionally substituted acyl, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, and optionally substituted heteroaryl; eachinstance of R^(A2) is independently selected from hydrogen, deuterium,halogen, —CN, optionally substituted acyl, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl,—OR^(A2a), —N(R^(A2a))₂, and —SR^(A2a), wherein each occurrence ofR^(A2a) is independently selected from hydrogen, optionally substitutedacyl, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl, andoptionally substituted heteroaryl, or any two R^(A1), any two R^(A2), orone R^(A1) and one R^(A2) are joined to form an optionally substitutedcarbocyclic, optionally substituted heterocyclic, optionally substitutedaryl, or optionally substituted heteroaryl ring; each X is independentlyselected from N and CH, wherein at least one X is N; W is selected fromN and C(R^(1a)); each of R^(1a), if present, and R^(1b) is independentlyselected from hydrogen, deuterium, halogen, optionally substituted acyl,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, —CN, —OR^(B1a), —N(R^(B1a))₂, and —SR^(B1a),wherein each occurrence of R^(B1a) is independently selected fromhydrogen, optionally substituted acyl, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, and optionally substituted heteroaryl, orR^(1a) and R^(1b) are joined to form an optionally substitutedcarbocyclic, optionally substituted heterocyclic, optionally substitutedaryl, or optionally substituted heteroaryl ring; R² is an optionallysubstituted C₁-C₄ alkylene or an optionally substituted C₂-C₄ alkenyleneor alkynylene, wherein one or more methylene units of the alkylene,alkenylene or alkynylene are optionally and independently replaced with—O—, —S—, or —N(R⁷)—; R³ is selected from a bond, an optionallysubstituted C₁-C₄ alkylene, and an optionally substituted C₂-C₄alkenylene or alkynylene, wherein one or more methylene units of thealkylene, alkenylene or alkynylene is optionally and independentlyreplaced with —O—, —S—, —N(R⁷)—, or —S(O)₂—; R⁴ is selected from —C₁-C₈alkyl, —O—C₁-C₈ alkyl, —NH₂, —NH(C₁-C₈ alkyl), —N(C₁-C₈ alkyl)₂, whereineach alkyl in R⁴ is optionally and independently substituted. each R⁵,if present, is independently selected from deuterium, halogen,optionally substituted acyl, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, —OR^(D1),—N(R^(D1))₂, and —SR^(D1), wherein each occurrence of R^(D1) isindependently selected from hydrogen, optionally substituted acyl,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, and optionally substituted aryl, optionallysubstituted heteroaryl; each R⁶, if present, is independently selectedfrom the group consisting of deuterium, halogen, optionally substitutedacyl, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, ═O, —CN, —OR^(C1), —N(R^(C1))₂, and—SR^(C1), wherein each occurrence of R^(C1) is independently selectedfrom the group consisting of hydrogen, optionally substituted acyl,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, a nitrogen protecting group when attached to anitrogen atom, an oxygen protecting group when attached to an oxygenatom, and a sulfur protecting group when attached to a sulfur atom, ortwo R^(C1) groups are joined to form an optionally substitutedheterocyclic ring; or two R⁶ are taken together to form a first 5-7membered, optionally substituted, heterocyclyl or carbocyclyl ring fusedto the ring to which the R⁶ are bound, wherein two substituents on thesubstituted heterocyclyl or carbocyclyl ring, or one substituent on thesubstituted heterocyclyl or carbocyclyl ring and a third R⁶ may be takentogether with the atoms to which they are bound to form a secondoptionally substituted, heterocyclyl or carbocyclyl ring fused to thering to the first optionally substituted, heterocyclyl or carbocyclylring and/or the ring to which the third R⁶ is bound; each R⁷ isindependently selected from hydrogen, and optionally substituted —C₁-C₆alkyl; n is 0, 1, 2, 3, 4, 5 or 6; and p is 0, 1, 2 or 3; and b) apharmaceutically acceptable excipient.
 19. A method of treating asubject suffering from a disease or condition associated with aberrantactivity of a CDK, comprising the step of administering to the subjectin need thereof a composition of claim
 18. 20. The method of claim 19,wherein the subject is suffering from a disease or condition associatedwith aberrant activity of CDK7.
 21. The method of claim 19, wherein thedisease or condition is selected from cancer, benign neoplasm,angiogenesis, inflammatory disease, autoinflammatory disease, autoimmunedisease, and an infectious disease.
 22. The method of claim 19, whereinthe subject is a mammal.